Kainate receptors and synaptic transmission - CiteSeerX

Progress in Neurobiology 70 (2003) 387–407

Kainate receptors and synaptic transmission

James E. Huettner∗Department of Cell Biology and Physiology, Washington University School of Medicine,

660 South Euclid Avenue, St. Louis, MO 63110, USA

Received 20 February 2003; accepted 25 July 2003

Abstract

Excitatory glutamatergic transmission involves a variety of different receptor types, each with distinct properties and functions. Physiolog-ical studies have identified both post- and presynaptic roles for kainate receptors, which are a subtype of the ionotropic glutamate receptors.Kainate receptors contribute to excitatory postsynaptic currents in many regions of the central nervous system including hippocampus,cortex, spinal cord and retina. In some cases, postsynaptic kainate receptors are co-distributed with�-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) andN-methyl-d-aspartate (NMDA) receptors, but there are also synapses where transmission is mediatedexclusively by postsynaptic kainate receptors: for example, in the retina at connections made by cones onto off bipolar cells. Modulationof transmitter release by presynaptic kainate receptors can occur at both excitatory and inhibitory synapses. The depolarization of nerveterminals by current flow through ionotropic kainate receptors appears sufficient to account for most examples of presynaptic regulation;however, a number of studies have provided evidence for metabotropic effects on transmitter release that can be initiated by activation ofkainate receptors. Recent analysis of knockout mice lacking one or more of the subunits that contribute to kainate receptors, as well asstudies with subunit-selective agonists and antagonists, have revealed the important roles that kainate receptors play in short- and long-termsynaptic plasticity. This review briefly addresses the properties of kainate receptors and considers in greater detail the physiological analysisof their contributions to synaptic transmission.© 2003 Elsevier Ltd. All rights reserved.

Contents

1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3882. Kainate receptor properties. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3883. Kainate receptor distribution and function. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390

3.1. Hippocampus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3903.1.1. Presynaptic receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3903.1.2. Postsynaptic receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3953.1.3. Transgenic mice. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3963.1.4. Synaptic plasticity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398

3.2. Cortex. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3983.3. Amygdala. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3993.4. Retina. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3993.5. Striatum. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4003.6. Hypothalamus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400

Abbreviations: GYKI53655, 1-(4-aminophenyl)-3-methylcarbamyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine; SYM2081, 2S,4R-4-methylglutamate; SYM2206, (±)-4-(4-aminophenyl)-1,2-dihydro-1-methyl-2-propylcarbamoyl-6,7-methylenedioxyphthalazine; CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione; APV, 2-amino-5-phosphono-valerate; NMDA,N-methyl-d-aspartate; CPCCOEt, 7-(hydroxyimino)cyclopropa[β]-chromen-1�-carboxylate ethylester; AMPA,�-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; ATPA, (RS)-2-amino-3-(3-hydroxy-5-tertbutylisoxazol-4-yl)propanoic acid; DRG, dorsal root ganglion;trans-PDC, trans-pyrrolidine-2,4-carboxylic acid; TTX, tetrodotoxin

∗ Tel.: +1-314-362-6624; fax:+1-314-362-7463.E-mail address: [email protected] (J.E. Huettner).

URL: http://www.cellbio.wustl.edu/faculty/huettner/.

0301-0082/$ – see front matter © 2003 Elsevier Ltd. All rights reserved.doi:10.1016/S0301-0082(03)00122-9

388 J.E. Huettner / Progress in Neurobiology 70 (2003) 387–407

3.7. Cerebellum. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4003.8. Spinal cord. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4013.9. Dorsal root ganglia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401

4. Perspectives. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402

1. Introduction

Kainate receptors are one of three subtypes of ionotropicreceptors for the excitatory transmitterl-glutamate(Dingledine et al., 1999). The other two subtypes, whichare named for the synthetic agonistsN-methyl-d-aspartate(NMDA) and�-amino-3-hydroxy-5-methyl-4-isoxazolepro-pionic acid (AMPA), are known to mediate postsynapticcurrents at excitatory synapses throughout the brain andspinal cord (Mayer and Westbrook, 1987). The physiologi-cal properties of kainate receptors (Chittajallu et al., 1999;Lerma et al., 2001), and their roles in synaptic transmission(Frerking and Nicoll, 2000; Kullmann, 2001; Lerma, 2003),have been discerned only recently, following the discoveryof selective antagonists that allow for isolation of kainatereceptor-mediated currents (Paternain et al., 1995; Wildingand Huettner, 1995; Bleakman et al., 1996a). Additionalinterest in kainate receptors has been raised by the cloningand characterization of their subunit cDNAs (Hollmannand Heinemann, 1994), and by the recognition that kainatereceptor subunits are distinct from subunits that contributeto AMPA receptors (Boulter et al., 1990; Keinänen et al.,1990) and to NMDA receptors (Kutsuwada et al., 1992;Monyer et al., 1992; Moriyoshi et al., 1991).

2. Kainate receptor properties

Kainate receptors were originally defined by Watkins andcoworkers (Davies et al., 1979; Watkins and Evans, 1981)based on the pharmacology of neuronal responses to excita-tory amino acids. In particular, the selective depolarizationof isolated dorsal root fibers by kainate led them to proposea unique receptor for kainate that was distinct from the bind-ing sites activated by NMDA and AMPA.1 Subsequent workhas confirmed the existence of three different receptor sub-types (Hollmann and Heinemann, 1994; Dingledine et al.,1999), although it also has been recognized that many ex-citatory amino acids, including kainate and AMPA, are notentirely selective for only one receptor class. Thus, kainateactivates AMPA receptors to produce large sustained cur-

1 The original classification proposed by Watkins and coworkers iden-tified NMDA, kainate and quisqualate receptors; however, AMPA wassubsequently recognized as a more selective agonist than quisqualate andthe classification was revised (seeMonaghan et al., 1989; Watkins et al.,1990).

rents (Kiskin et al., 1986; Keinänen et al., 1990; Patneau andMayer, 1991), and AMPA can activate at least some typesof kainate receptor (Herb et al., 1992).

There are five different subunits that contribute to kainatereceptors (Hollmann and Heinemann, 1994). They fall intotwo families, based on sequence homology and agonist bind-ing properties. GLUK5, GLUK6 and GLUK7

2 are approxi-mately 70% identical (Bettler et al., 1990, 1992; Egebjerget al., 1991; Sommer et al., 1992). The GLUK1 and GLUK2subunits also are 70% identical (Werner et al., 1991; Herbet al., 1992; Sakimura et al., 1992), but share only 40%identity with GLUK5, GLUK6 and GLUK7. Both familiesof kainate receptor subunits also display weaker identitywith subunits of AMPA (30–35%) and NMDA receptors(10–20%). In addition, all of the glutamate receptor sub-units are thought to adopt the same membrane topology. Theamino terminal half of each subunit is extracellular. Thereare four hydrophobic segments: three membrane spanningdomains and a “p-loop” that dips into the membrane fromthe cytoplasmic face to form the pore (Hollmann et al., 1994;Roche et al., 1994; Bennett and Dingledine, 1995).

The GLUK5 and GLUK6 subunits, but not the otherkainate receptor subunits, can undergo mRNA editing thatchanges an amino acid in the channel pore and regulates per-meation properties (Sommer et al., 1991). For both GLUK5and GLUK6, as well as the GLUA2 subunit of AMPA recep-tors, the genomic sequence encodes a glutamine residue inthe edited location in the p-loop that is converted by editingto code for an arginine (Sommer et al., 1991). In all threecases, mature receptors comprised of unedited subunits dis-play inwardly rectifying current–voltage (I–V) relations ow-ing to block of outward current by intracellular polyamines,whereas receptors including edited subunits resist polyamineblock and have linearI–V relations (Bowie and Mayer,1995; Kamboj et al., 1995; Isa et al., 1995; Donevan andRogawski, 1995; Koh et al., 1995; Bähring et al., 1997).Editing at the Q/R site also determines single channelconductance and calcium permeability. Fully uneditedreceptors exhibit a higher relative calcium permeability(Egebjerg and Heinemann, 1993; Burnashev et al., 1995,1996) and a higher unitary conductance (Howe, 1996;Swanson et al., 1996) as compared to receptors that includeone or more edited subunits. In addition to the Q/R site, the

2 IUPHAR nomenclature (Lodge and Dingledine, 2000) used throughoutthis review. Previous designations: GLUK1, KA1; GLUK2, KA2; GLUK5,GluR5; GLUK6, GluR6; GLUK7, GluR7.

J.E. Huettner / Progress in Neurobiology 70 (2003) 387–407 389

GLUK6 subunit also displays two additional sites of RNAediting in the first transmembrane domain (Köhler et al.,1993).

Agonist binding to glutamate receptor subunits involvesregions in the N-terminal domain and the extracellulardomain between the last two transmembrane segments(Kuusinen et al., 1995; Stern-Bach et al., 1994; Armstronget al., 1998; Armstrong and Gouaux, 2000). Many ofthe glutamate receptor subunit mRNAs can be alternatelyspliced, resulting in structural diversity among mature re-ceptors (Hollmann and Heinemann, 1994). For example,the GLUK5 subunit N-terminal domain can either includeor lack a 15 amino acids segment encoded by an alternatelyspliced exon (Bettler et al., 1990). In addition, the carboxyterminal domains of GLUK5, GLUK6 and GLUK7 displayalternate splicing that alters their length and, in some cases,their terminal residues (Sommer et al., 1992; Gregor et al.,1993; Schiffer et al., 1997). For several of the glutamatereceptor subunits, the cytoplasmic carboxy terminus isknown to contain sites for phosphorylation (Dingledineet al., 1999) that may serve to regulate channel function(Raymond et al., 1993; Wang et al., 1993; Dildy-Mayfieldand Harris, 1994; Traynelis and Wahl, 1997; Ghetti andHeinemann, 2000). In addition, the GLUK6 subunit can bepalmitoylated at two cysteine residues located in the carboxyterminal domain (Pickering et al., 1995). Specific interac-tions with modulatory proteins also have been described forcarboxy terminal domains of individual glutamate receptorsubunits. For example, several of the subunits, includingGLUK6, can interact with proteins that contain specific PDZdomains (Garcia et al., 1998; Hirbec et al., 2003). Suchinteractions are thought to coordinate the joint synaptic lo-calization of receptors with other PDZ domain-containingproteins into functional complexes (Savinainen et al., 2001;Sheng and Pak, 2000; Mehta et al., 2001; Coussen et al.,2002).

A great deal has been learned from studies in whichkainate receptor subunits were expressed inXenopusoocytes or in transfected HEK 293 cells. GLUK5, GLUK6and GLUK7 are capable of forming functional homomericligand-gated channels when expressed in isolation (Bettleret al., 1990; Egebjerg et al., 1991; Sommer et al., 1992;Schiffer et al., 1997). Binding of radioactive ligands tothese homomeric receptors indicate dissociation constantsfor kainate in the range of 50–100 nM (Bettler et al., 1992;Lomeli et al., 1992; Sommer et al., 1992; Schiffer et al.,1997). When the GLUK1 and GLUK2 subunits are expressedin isolation they form high affinity binding sites for kainate,with dissociation constants in the range of 5–15 nM (Werneret al., 1991; Herb et al., 1992). In contrast to GLUK5,GLUK6 and GLUK7, however, GLUK1 and GLUK2 do notform detectable homomeric channels when expressed alonein oocytes or in mammalian cells. Co-expression studies(Herb et al., 1992; Sakimura et al., 1992) have demon-strated the formation of heteromeric channels that includethe GLUK2 subunit together with GLUK5 or GLUK6. Less

work has been done on heteromeric channels that includethe GLUK1 subunit.

Binding studies have documented both high and lowaffinity sites (KD ∼ 5 and 50 nM for [3H]kainate, respec-tively) in rat brain membranes (London and Coyle, 1979;Unnerstall and Wamsley, 1983; Hampson et al., 1987). Ithas been proposed that high affinity receptors may corre-spond to heteromeric assemblies that included the GLUK1or GLUK2 subunits, whereas receptors lacking GLUK1 orGLUK2 would exhibit lower affinity (Contractor et al.,2003). On the other hand, recombinant heteromeric recep-tors that include GLUK1 or GLUK2 typically display muchlower agonist affinity when expressed in vitro than the ho-momeric binding sites formed by expression of GLUK1 orGLUK2 in isolation (Herb et al., 1992; Pemberton et al.,1998). For example,3H-kainate binds to GLUK2/GLUK5heteromers with aKD of 90 nM, as compared to 15 nM forGLUK2 homomers or 73 nM for GLUK5 homomers (Herbet al., 1992). Further work is needed to resolve the subunitcomposition of high affinity binding sites in native mem-branes, as it is not clear what function the high affinitysites would serve if they represent homomeric assembliesof GLUK1 or GLUK2.

More recently, several groups have presented evidencethat GLUK5 and GLUK6 can co-assemble into heteromericchannels (Bortolotto et al., 1999; Cui and Mayer, 1999;Paternain et al., 2000). These studies took advantage of thefact that inclusion of a subunit with an R at the Q/R editingsite will significantly reduce polyamine block of outwardcurrent. Thus, co-expression of GLUK5(Q) with GLUK6(R)yields receptors that display little or no inward rectifica-tion, but which are sensitive to the GLUK5-selective com-pounds ATPA and LY382884 (Clarke et al., 1997; Lauridsenet al., 1985; O’Neill et al., 1998). Similar results were ob-tained upon co-expression of GLUK5(R) with GLUK6(Q).In addition,Cui and Mayer (1999)demonstrated functionalco-assembly of GLUK7 with either GLUK5 or GLUK6. Thus,a large number of distinct kainate receptor subtypes couldbe assembled based on the combinatorial mixing of five dif-ferent subunits.

The distribution of cells expressing kainate receptor mR-NAs has been mapped by in situ hybridization (Wisdenand Seeburg, 1993; Bahn et al., 1994; Tölle et al., 1993;Paternain et al., 2000; Bureau et al., 1999). In addition,several laboratories have used RT-PCR to determine sub-unit expression in individual neurons (Ruano et al., 1995;Ghasemzadeh et al., 1996; Porter et al., 1998; Cauli et al.,2000; Dai et al., 2002) or small populations of cells isolatedfrom specific regions (Belcher and Howe, 1997; Sahara et al.,1997; Paarmann et al., 2000). By in situ hybridization, cellsdisplaying prominent expression of the GLUK5, GLUK6,GLUK7, and GLUK2 kainate receptor subunits are distributedthroughout the CNS including cortex, striatum, hippocam-pus and cerebellum. Notable expression of the GLUK1 sub-unit is observed primarily in hippocampal CA3 and dentategranule neurons, whereas message for GLUK2 appears to be


more abundant and more widespread than for GLUK1 or theother subunits. Interested readers should refer to the originalliterature for detailed descriptions of expression in specificcell types (Bettler et al., 1990; Egebjerg et al., 1991; Werneret al., 1991; Lomeli et al., 1992; Wisden and Seeburg, 1993;Bahn et al., 1994; Tölle et al., 1993; Paternain et al., 2000;Bureau et al., 1999).

Analysis of receptors expressed by neurons in culture orin situ confirms that native receptors are, in fact, heteroge-neous. Cells from different regions of the nervous systemexpress kainate receptors with distinct physiological andpharmacological properties (Wilding and Huettner, 2001).Features common among all neuronal kainate receptors in-clude activation by micromolar concentrations of domoateand kainate (Lerma et al., 1993; Paternain et al., 1998;Wilding and Huettner, 1997), activation and potent desen-sitization by 4-methylglutamate, SYM2081 (Jones et al.,1997; Donevan et al., 1998), and blockade by lanthanum(Huettner et al., 1998) and by the competitive antagonistCNQX (Wilding and Huettner, 1995; Paternain et al., 1996).Differences exist from one cell type to the next in theexact potency of specific agonists for receptor activationor desensitization, and in the effect of GLUK5-selectiveagonists and antagonists (Kerchner et al., 2001a; Wildingand Huettner, 2001). In nearly all cases, it remains to bedetermined whether these differences in receptor propertiesbetween cell types arise from differential subunit expres-sion, alternate splicing, interaction with cell type specificaccessory proteins or some combination of these possibili-ties. Recently, progress in defining the subunit compositionof kainate receptors in specific cell types has been madeusing subunit-selective drugs and knockout mice defi-cient in expression of particular kainate receptor subunits(discussed below), but much more work is needed to de-fine the structural basis for heterogeneity of endogenousreceptors.

Table 1Selected pharmacological agents for kainate receptor analysis

APV Competitive antagonist of NMDA receptorsATPA Agonist selective for GLUK5, but also able to activate AMPA receptors and GLUK6/GLUK2 heteromers with lower potencyCNQX Competitive antagonist of AMPA and kainate receptorsConcanavalin A Lectin that inhibits kainate receptor desensitizationCyclothiazide Allosteric regulator that potentiates AMPA receptorsDomoate Kainate receptor agonist producing less desensitization than kainateGlutamate Endogenous transmitter and agonist for kainate, AMPA, NMDA and mGluRsGYKI52466 Non-competitive antagonist selective for AMPA receptors, but not as potent or as selective as GYKI53655GYKI53655 Non-competitive antagonist selective for AMPA receptorsKainate Kainate receptor agonist, but also activates AMPA receptorsLY293558 Competitive antagonist selective for GLUK5, but also an AMPA receptor antagonistLY294486 Competitive antagonist selective for GLUK5, but also a weak AMPA receptor antagonistLY377770 Active isomer of LY294486LY382884 Competitive antagonist selective for GLUK5

NBQX Competitive antagonist of AMPA and kainate receptorsNS102 Antagonist selective for kainate receptors, but with limited solubility in physiological solutionsSYM2081 Agonist selective for kainate receptors that produces strong, persistent desensitizationSYM2206 Non-competitive antagonist for AMPA receptors comparable to GYKI53655

Selectivity of additional compounds provided in the text.

3. Kainate receptor distribution and function

3.1. Hippocampus

Detailed study of the role of kainate receptors in synap-tic transmission has only been possible since the discoveryof selective AMPA receptor antagonists in 1995 (Paternainet al., 1995; Wilding and Huettner, 1995; Bleakman et al.,1996a). Before that time, a number of reports described in-teresting effects on excitability (Robinson and Deadwyler,1981; Westbrook and Lothman, 1983) and synaptic trans-mission (Collingridge et al., 1983; Kehl et al., 1984; Fisherand Alger, 1984) following exposure to low doses of kainate.It seems likely that kainate receptors mediated many of theseeffects, particularly in experiments that used submicromolarconcentrations of kainate; however, the possibility remainsthat both AMPA and kainate receptors were activated duringexposure to the agonist in these early studies. With the ad-vent of GYKI53655, and other selective AMPA and kainatereceptor antagonists, it became possible to define the sepa-rate contributions of kainate, AMPA and NMDA receptors(seeTable 1andBleakman and Lodge, 1998). Many of theinitial studies focused on hippocampal neurons.

3.1.1. Presynaptic receptorsThe first direct evidence for involvement of kainate re-

ceptors in synaptic transmission demonstrated a presynapticreduction in transmitter release by Schaffer collaterals ontoCA1 neurons upon the activation of kainate receptors inacute hippocampal slices (Chittajallu et al., 1996). Subse-quent studies reported a similar reduction in transmissionevoked from hippocampal GABAergic interneurons (Clarkeet al., 1997; Rodriguez-Moreno et al., 1997). In addition,evidence was obtained that postsynaptic kainate receptorscontribute to the EPSC at mossy fiber synapses (Vignes andCollingridge, 1997; Castillo et al., 1997; Mulle et al., 1998)


and at excitatory synapses onto interneurons (Cossart et al.,1998; Frerking et al., 1998).

In order to study the presynaptic actions of kainate,slices or cultures are equilibrated with a selective AMPAantagonist. GYKI53655 or SYM2206 at 100�M pro-vide complete non-competitive blockade of AMPA recep-tors (Paternain et al., 1995; Wilding and Huettner, 1995;Pelletier et al., 1996; Bleakman et al., 1996a), while caus-ing only slight reduction in currents mediated by kainatereceptors (Wilding and Huettner, 2001). Driven by the lim-ited availability of GYKI53655 some investigators haveemployed lower doses of GYKI53655 (40–50�M), or usedthe less selective, but commercially available, compoundGYKI52466. Under these conditions, currents mediated byAMPA receptors will be significantly reduced but may notbe totally abolished (Donevan et al., 1994; Paternain et al.,1995; Wilding and Huettner, 1995). To study transmissionat excitatory synapses with AMPA receptors blocked, mag-nesium can be removed from the medium revealing theNMDA receptor-mediated component of excitatory post-synaptic current (Davies and Collingridge, 1989; Hestrinet al., 1990). For study of evoked IPSCs, both AMPA andNMDA receptors can be blocked. Using these conditions,superfusion of kainate, domoate or other kainate recep-tor agonists produces a reduction in postsynaptic current,which recovers when the agonist is removed. This effecton transmission is sensitive to block by CNQX, indicat-ing a dependence on kainate receptor activation. However,because kainate might stimulate release of endogenoustransmitters, including glutamate, well-controlled studiesuse antagonists for a number of additional receptors such asGABAB, adenosine, and metabotropic glutamate receptorsto limit the possibility of indirect effects.

As discussed throughout this review, exposure to kainatereceptor agonists can produce significantly different resultsdepending on the agonist concentration. This observationhas led some authors to question the physiological relevanceof effects observed with kainate concentrations above 1�M(Ben-Ari and Cossart, 2000). To allow readers to draw theirown conclusions, the concentrations of both agonists andantagonists are provided for each specific experimental re-sult discussed. Most of the studies cited have included con-trol experiments to mitigate possible non-selective actionsof kainate. In addition, steady-state concentration-responseanalysis indicates that 20–30�M kainate is needed to pro-duce half-maximal activation of whole-cell currents in iso-lated neurons (Lerma et al., 1993; Paternain et al., 1998;Wilding and Huettner, 1997), suggesting that doses greaterthan 1�M might be required to achieve significant receptoractivation during slow perfusion of intact tissue slices.

3.1.1.1. Excitatory synapses. Chittajallu et al. (1996)were the first to provide direct evidence that presynaptickainate receptors may modulate release of glutamate. Theyshowed that exposure to kainate produced a dose-dependentreduction in K+-stimulated release of [3H]glutamate from

pre-loaded rat hippocampal synaptosomes. The IC50 forkainate was 27�M, and there was no effect of kainate onbasal release in normal K+. NS102 (10�M) and CNQX(30�M) partially overcame the inhibition of release bykainate; however, NBQX (10�M) GYKI52466 (100�M)and cyclothiazide (100�M) had little or no effect on thisaction of kainate. In physiological recordings from CA1neurons in rat hippocampus,Chittajallu et al. (1996)mon-itored NMDA receptor-mediated EPSCs in the presenceof GYKI52466 (100�M). Exposure to 1–30�M kainateelicited an initial burst of spontaneous EPSCs but then pro-duced a sustained reduction in EPSCs evoked by stimulationof Schaffer collateral fibers. Domoate had a similar action at100 nM, whereas 300 nM kainate only caused a modest en-hancement of evoked transmission, and 100 nM kainate hadno effect. These effects of kainate were not blocked by an-tagonists of GABAA (50�M picrotoxin), GABAB (10�MCGP55845) or adenosine A1 (0.1�M DPCPX) receptors.

Similar results were obtained byKamiya and Ozawa(1998), who also studied synapses formed by Schaffercollaterals onto CA1 neurons in 14–21-day-old rats. Inthis study, presynaptic calcium transients were monitoredby labeling the Schaffer collateral fibers with rhod-2AM.Bath applications of 1�M kainate reduced the postsynapticEPSC and the presynaptic calcium signal in parallel. Inaddition, paired pulse facilitation was enhanced during ex-posure to kainate. Such changes in paired pulse modulationare believed to be a reliable indicator of a presynaptic locusof regulation.Kamiya and Ozawa (1998)repeated these ob-servations in the presence of picrotoxin to block ionotropicGABAA receptors and thus reduce the possibility of indirecteffects mediated by an action of kainate on interneurons(but see below). They also showed that kainate did notaffect the presynaptic fiber volley and that the effects ofkainate were reduced by NS102 (Verdoorn et al., 1994).

Subsequent work byFrerking et al. (2001)confirmed andextended the evidence for presynaptic modulation of releaseby demonstrating a reduction in quantal content duringexposure to 200 nM domoate. To determine whether depo-larization of presynaptic fibers was required for this form ofmodulation,Frerking et al. (2001)compared the action ofdomoate with increases in extracellular KCl. Concentrationsof KCl that were sufficient to inhibit evoked release causeda comparable reduction in the presynaptic fiber volley andan increase in the frequency of mEPSCs, whereas domoatehad neither effect. Thus, although a high concentrationof domoate (20�M) was shown to be capable of causingsignificant depolarization, depolarization of presynapticterminals was not essential for modulation of release by200 nM domoate. Instead, the effect of domoate on evokedrelease was suppressed by inhibitors normally associatedwith metabotropic receptors, including pertussis toxin andthe protein-modifying reagentN-ethylmaleimide. Evidencefor metabotropic actions via kainate receptors has also beenobtained for inhibitory nerve terminals in hippocampal areaCA1 (Rodriguez-Moreno and Lerma, 1998; and see below)


and for postsynaptic regulation of potassium current thatunderlies the slow afterhyperpolarization (IsAHP) in CA1pyramidal cells (Melyan et al., 2002). Although the exactmechanisms whereby kainate receptors elicit metabotropiceffects are not clear,Frerking et al. (2001)argue that thepresynaptic action of kainate and domoate on Schaffer col-lateral fiber transmission is likely to be direct, rather than anindirect action of metabotropic neuromodulators releasedfrom interneurons. Their evidence for a direct action onexcitatory fibers included the inability to prevent regula-tion by a cocktail of antagonists to known neuromodula-tors as well as the demonstration that solutions containinghigh divalent ion concentrations (8 mM Ca2+ and 17 mMMg2+) were able to block interneuron spiking elicited bykainate receptor agonists, but did not prevent regulationof Schaffer collateral transmission. On the other hand, insome (Mulle et al., 2000; Cossart et al., 2001), but not all(Frerking et al., 1999; Jiang et al., 2001; Rodriguez-Morenoet al., 1997), studies of hippocampal area CA1, exposure tokainate was found to stimulate quantal release from someinterneurons during action potential blockade by TTX (seebelow), raising the possibility that kainate-evoked release ofa metabotropic neuromodulator may not have been entirelyeliminated by elevating the divalent ion concentrations.There is clearly a need for more work to explore the po-tential coupling mechanism between kainate receptors andNEM- or pertussis toxin-sensitive effectors.

In addition to the Schaffer collateral-commissuralsynapses onto CA1 neurons, the role of presynaptic kainatereceptors has also been examined at mossy fiber synapsesformed by dentate granule cells onto CA3 pyramidal neu-rons (Vignes et al., 1998; Kamiya and Ozawa, 2000; Schmitzet al., 2000). In this case, incubation with 200 nM kainatealters the presynaptic fiber volley, increasing the excitabil-ity of presynaptic fibers but reducing the calcium influxelicited by orthodromic action potentials.Schmitz et al.(2000) examined the effect of kainate on fiber excitabilityin detail. Low doses of kainate were found to enhance theorthodromic fiber volley as well as the firing of spikes bygranule cells in response to antidromic stimulation of mossyfibers. A higher dose of kainate (10�M) caused an initialincrease in the fiber volley followed by a prolonged periodof fiber volley suppression that significantly outlasted theperiod of exposure to kainate. Elevation of extracellularK+, from endogenous sources, during exposure to kainatewas not sufficient to account for these changes in fiberexcitability (Schmitz et al., 2000). Interestingly, these ini-tial studies found that even conditions that elevated fiberexcitability nevertheless caused a reduction in the strengthof transmission (see below). The amplitude of field EPSPs(Kamiya and Ozawa, 2000), or whole-cell EPSCs (Vigneset al., 1998), recorded in the absence of NMDA or AMPAreceptor antagonists was reduced by∼60% during expo-sure to 0.2–1�M kainate. In addition, release of glutamateupon stimulation of associational/commissural fibers wasshown to cause heterosynaptic inhibition of mossy fiber

transmission and to enhance the fiber volley, presumably byactivation of presynaptic kainate receptors (Schmitz et al.,2000).

More recent work (Schmitz et al., 2001a,b; Contractoret al., 2001; Lauri et al., 2001a,b; Kamiya et al., 2002), how-ever, has modified and extended the initial interpretation ofthe role that presynaptic kainate receptors play at mossyfiber synapses. Whereas initial studies focused on the inhi-bition produced by exogenous kainate at 200 nM and above,subsequent work has revealed evidence for potentiation ofmossy fiber transmission (see alsoKehl et al., 1984), eitherby low concentrations of kainate (50 nM) or by release of en-dogenous glutamate during short-term frequency-dependentplasticity. Schmitz et al. (2001a)found that 50 nM kainatecaused a 50–100% enhancement in mossy fiber transmis-sion, an effect that was mimicked by mild depolarizationwith 4 mM KCl. Full dose response curves for kainate andKCl demonstrated a striking parallel in their effects on EPSCamplitude and afferent fiber volleys. Low effector concen-trations enhanced both of these parameters. EPSC ampli-tude increased to a peak at 50 nM kainate or 4 mM KCl, butwas reduced relative to baseline for higher concentrationsof either agent. Effects on fiber volley amplitude showed asimilar trend, but were displaced to higher concentrations,reaching maximal enhancement at 500 nM kainate or 8 mMKCl and declining below baseline at higher doses.

Several groups (Schmitz et al., 2001a; Contractor et al.,2001; Lauri et al., 2001a) have now demonstrated a rolefor presynaptic kainate receptors in frequency-dependentfacilitation at mossy fiber synapses.Schmitz et al. (2001a)monitored the amplitude of NMDA receptor-mediatedEPSCs in the context of AMPA receptor blockade with20�M GYKI53655. Application of 10�M CNQX or50�M NBQX significantly blunted facilitation of EPSCselicited by repetitive stimulation at 25 or 100 Hz. In ad-dition, this study (Schmitz et al., 2001a) demonstratedheterosynaptic facilitation of mossy fiber synapses follow-ing a short tetanus (3 pulses/200 Hz) delivered to asso-ciational/commissural fibers.Schmitz et al. (2001a)alsoconfirmed, however, the occurrence of heterosynaptic de-pression for longer (10 pulses/200 Hz) or higher intensitystimulation (Schmitz et al., 2000). Lauri et al. (2001a)observed a similar reduction in frequency dependent facil-itation at mossy fiber synapses with the GLUK5-selectiveantagonist LY382884 (10�M). This reduction was not af-fected by 1�M CGP55845, a GABAB receptor antagonist,and was not mimicked by the protein kinase C (PKC) in-hibitor calphostin C, which attenuates effects ascribed tothe metabotropic action of kainate (Rodriguez-Moreno andLerma, 1998). Frequency-dependent facilitation at mossyfiber synapses has also been examined in subunit defi-cient mice (Contractor et al., 2001). Knocking out GLUK5caused little or no change in short-term plasticity, whereasdeletion of GLUK6 reduced paired pulse facilitation (PPF)for inter-pulse intervals less than 40 ms and significantlyreduced facilitation during brief tetani at 0.5–5 Hz. Optical


recordings of calcium elevation and membrane potentialalso support a role for presynaptic kainate receptors inpaired pulse facilitation (Kamiya et al., 2002). In this study(Kamiya et al., 2002), 10�M CNQX reduced PPF of presy-naptic calcium elevation and presynaptic afterdepolariza-tions to a much greater extent than did 100�M GYKI52466.Moreover, there was no significant effect on PPF by expo-sure to the GABAB receptor agonist baclofen (10�M), theA1 adenosine receptor agonist 2-chloroadenosine (10�M),or the group II mGluR agonist DCG-IV (1�M).

The pharmacological profile and subunit composition ofpresynaptic receptors that affect excitatory transmission inthe hippocampus remain controversial, both for mossy fibersarising from dentate granule cells and for the excitatory ax-ons of CA3 pyramidal cells. In both cases, Collingridgeand coworkers (Vignes et al., 1998; Bortolotto et al., 1999;Lauri et al., 2001a,b; Clarke and Collingridge, 2002) havesuggested that the presynaptic receptors include a GLUK5subunit. Their initial results (Vignes et al., 1998; Bortolottoet al., 1999) demonstrated that the GLUK5-selective ag-onist ATPA was equally effective as kainate at reducingtransmission by mossy fibers and associational/commissuralfibers onto CA3 pyramidal neurons, or by Schaffer collat-eral/commissural fibers onto pyramidal cells in CA1 (Vigneset al., 1998). In subsequent work (Clarke and Collingridge,2002), inhibition by ATPA of excitatory transmission in areaCA1 was found to be independent of GABAA, GABAB,muscarinic or adenosine A1 receptor activation, suggestingthat ATPA may act directly on excitatory terminals. On theother hand, a number of differences were noted between theeffects of ATPA and kainate on transmission in area CA1(Clarke and Collingridge, 2002): first, the GLUK5 selectiveantagonist LY382884 was effective at blocking the actionof ATPA, but was weaker against kainate. Second, elevatedCa2+ depressed the effect of ATPA, but not kainate. Third,kainate, but not ATPA, enhanced excitability of the CA1neurons. Together, these findings raise the possibility thatATPA and kainate influence excitatory transmission via dis-tinct mechanisms. Additional evidence for differences be-tween the actions of ATPA and kainate also comes fromwork on mossy fiber synapses.Schmitz et al. (2000)foundthat, in contrast to kainate, ATPA did not alter the affer-ent fiber volley at mossy fiber synapses (see alsoVigneset al., 1998). Moreover, the reduction in mossy fiber trans-mission produced by ATPA, but not kainate, was blocked bythe GABAB receptor antagonist SCH50911 (20�M), sug-gesting that ATPA may exert its effect indirectly by stimu-lating interneurons to fire and release GABA, which wouldthen act on presynaptic GABAB receptors on the mossyfiber terminals (Schmitz et al., 2000). This interpretation hasbeen contested byLauri et al. (2001b), however, who per-formed similar experiments and observed no effect of 20�MSCH50911 on the ability of ATPA to suppress transmissiononto CA3 neurons either by mossy fibers or by associa-tional/commissural fibers. These results (Lauri et al., 2001b)would be consistent either with a direct effect on mossy

fibers by ATPA or an indirect effect mediated by some agentother than, or in addition to, GABA. As mentioned above,the ability of LY382884 to block modulation by exogenousATPA and to inhibit both short-term (Lauri et al., 2001a)and long-term (Bortolotto et al., 1999) plasticity at mossyfiber synapses argues that GLUK5 contributes to receptorsinvolved in presynaptic modulation at excitatory synapses.On the other hand, compelling evidence that the GLUK5 sub-unit is not absolutely required for presynaptic modulationof mossy fibers, or associational/commissural fibers, comesfrom studies demonstrating a persistence of modulation inslices from GLUK5-deficient mice (Contractor et al., 2000,2001; seeSection 3.1.3).

3.1.1.2. Inhibitory synapses. In addition to the presynap-tic actions of kainate just described, kainate receptors alsohave been implicated in regulating the evoked release ofGABA from inhibitory interneurons. Early studies (Fisherand Alger, 1984; Kehl et al., 1984) showed that 0.3–1�Mkainate reduced the amplitude of spontaneous and evokedIPSPs recorded in both CA1 and CA2/CA3 pyramidal cells(see alsoSloviter and Damiano, 1981). More recent work,using AMPA-selective antagonists, has confirmed this ef-fect and demonstrated that it involves kainate receptors. Allof the groups that have studied the action of kainate on in-hibitory transmission in hippocampus agree that exposureto micromolar concentrations of kainate causes inhibition ofevoked release (but seeMulle et al., 2000). There is disagree-ment, however, concerning the mechanism(s) that underliethis inhibition. In addition, similar to the work on excitatorytransmission, more recent studies have provided evidencefor enhancement of inhibitory transmission by submicromo-lar doses of kainate (Jiang et al., 2001; Cossart et al., 2001).

Clarke et al. (1997)recorded from CA1 neurons andshowed that evoked IPSPs were suppressed by 5�M kainateor by the GLUK5-selective agonist ATPA (10�M). More-over, the GLUK5-selective antagonist LY294486 preventedregulation of IPSPs by both kainate and ATPA. They alsoshowed that GABAA and GABAB receptor-mediated com-ponents of the IPSP were blocked to the same extent, andthat feedback mediated by GABAB autoreceptors was notrequired for kainate and ATPA to reduce inhibitory trans-mission. Lerma and coworkers (Rodriguez-Moreno et al.,1997) also have studied inhibitory inputs to CA1 neurons anddemonstrated a reduction in evoked IPSPs by superfusionwith kainate. The concentration-response relation for thiseffect was “bell-shaped”, suggesting that activated, but notdesensitized, receptors were responsible. The apparent EC50for kainate was 20�M, in agreement with work on kainatereceptor activation in cultured hippocampal neurons (Lermaet al., 1993; Wilding and Huettner, 1997). Modulation of IP-SCs declined at higher kainate doses with an apparent IC50 of370�M (cf. Paternain et al., 1998). Lerma’s group showedthat kainate increased the proportion of failures of evokedIPSCs, which suggests a presynaptic change in transmitterrelease probability. Moreover, exposure to kainate produced


changes in the IPSC’s coefficient of variation that are consis-tent with a presynaptic locus of change. Finally, they foundthat during treatment with kainate spontaneous miniatureIPSCs were reduced in frequency and somewhat reduced inamplitude, although this effect on miniature IPSCs has notbeen confirmed by most subsequent studies (e.g.Frerkinget al., 1998, 1999; but seeContractor et al., 2000; Behr et al.,2002).

Rodriguez-Moreno et al. (1997)have suggested thatkainate receptors on presynaptic GABAergic terminalsreduce transmitter release by a G-protein-mediated activa-tion of phospholipase C and PKC (see alsoZiegra et al.,1992; Cunha et al., 1997, 1999, 2000). They showed thatpre-incubation with pertussis toxin blocked the effect ofkainate on evoked IPSCs, as did exposure to the PKC in-hibitors staurosporine and calphostin C. It remains to bedetermined whether these metabotropic actions of kainateinvolve a direct coupling of kainate receptors to specificG-proteins or whether they result from an indirect mech-anism such as kainate-stimulated release of some otherendogenous compound which may then activate its ownG-protein-coupled receptor. Evidence for such an indirectmechanism involving adenosine has recently been obtainedin the striatum (see below).Rodriguez-Moreno et al. (2000)have tested for indirect modulation by other transmittersvia blockade with a cocktail of inhibitors to metabotropicglutamate receptors (MCPG and MPPG at 1.5 mM), opi-oid receptors (naloxone, 100�M), GABAB receptors(2-hydroxysaclofen, 50–150�M), and adenosine receptors(DPCPX, 0.1�M). Their results argue against involvementof endogenous agonists for these receptors, but do not ruleout the possibility that some other endogenous compoundmay produce indirect inhibition of evoked IPSCs.

Several studies have implicated kainate receptors onthe soma and dendrites of GABAergic interneurons in theregulation of evoked IPSC amplitude. Papers byCossartet al. (1998)and by Frerking et al. (1998)examined in-terneurons in area CA1 of rat hippocampal slices. Bothstudies demonstrated that activation of kainate receptorscaused an increase in interneuronal action potential firing.In the absence of TTX, exposure to kainate (0.25–10�M)increased the rate of spontaneous IPSCs recorded in pyra-midal cells, but at the same time decreased the amplitudeof IPSCs evoked by electrical stimulation (see alsoBureauet al., 1999). ATPA (1�M) was as effective as kainate intriggering action potentials (Cossart et al., 1998), whichis consistent with evidence from studies of knockout micefor GLUK5 expression by CA1 interneurons (Mulle et al.,2000). Both Frerking et al. (1998)andCossart et al. (1998)demonstrated a contribution by kainate receptors to post-synaptic excitatory inputs to interneurons and argued thatthese somatodendritic kainate receptors were responsiblefor the effects of kainate on evoked transmission. In sub-sequent work on guinea pig slices, however,Semyanov andKullmann (2001)have suggested that spike initiation duringexposure to kainate receptor agonists may occur primarily

in the axons of interneurons. In this study, spontaneousaction currents were recorded in interneurons under volt-age clamp during exposure to 1�M kainate. Frequency ofspontaneous action currents was largely insensitive to theholding potential, which suggests that they initiated in theaxon at a location that was electrically remote from thevoltage-clamped somato-dendritic compartment.

Whether kainate receptors are specifically localized tothe presynaptic terminals of inhibitory neurons that synapseon pyramidal cells remains controversial (Ben-Ari andCossart, 2000; Kullmann, 2001). Nicoll and coworkers(Frerking et al., 1999) have proposed that the reduction inevoked IPSCs recorded in pyramidal cells during exposureto kainate can be explained without invoking presynap-tic kainate receptors. They suggest that GABA releasedby the increase in spontaneous action potential firing actson postsynaptic GABAA receptors to shunt postsynap-tic current. Frerking et al. (1999)further proposed thatspontaneous release of GABA would activate presynapticGABAB receptors to reduce subsequent evoked release (seealsoKerchner et al., 2001b), althoughClarke et al. (1997)have reported that antagonism of GABAB receptors did notprevent the reduction in evoked IPSCs in area CA1. Ad-ditional postsynaptic shunting may be provided by kainatereceptors expressed by the pyramidal neurons (Bureauet al., 1999). On the other hand, Lerma and coworkers(Rodriguez-Moreno et al., 2000) have noted the lack ofcorrelation between the frequency of spontaneous IPSCselicited by different agonists and the extent of reduction inevoked IPSC amplitude. In particular, they observed thatlow doses of glutamate (3 and 10�M) suppressed evokedtransmission without any effect on the frequency of spon-taneous release events, whereas AMPA (50�M) greatlyincreased the spontaneous IPSC frequency, but had no ef-fect on the amplitude of evoked IPSCs. Kainate (0.3 and3�M) and ATPA (1 and 10�M) both enhanced sIPSC fre-quency and reduced eIPSC amplitude (Rodriguez-Morenoet al., 2000). Local synaptic release of glutamate by a con-ditioning train to excitatory fibers is sufficient to inhibitevoked IPSCs by a kainate receptor-dependent mechanism(Min et al., 1999), which would be consistent with a localeffect on inhibitory terminals. Such conditioning trains alsoenhance axonal excitability in interneurons (Semyanov andKullmann, 2001), however, so that a mechanism involvingelevated spontaneous release cannot be ruled out.

As noted above, several recent studies have reported anenhancement of inhibitory transmission by exposure to lowdoses of kainate (Jiang et al., 2001; Cossart et al., 2001).Cossart et al. (2001)recorded an increase in mIPSC fre-quency in CA1 interneurons during exposure to 250 nMkainate. This enhancement of spontaneous release was notblocked by 100�M cadmium, suggesting that it did not re-quire activation of voltage-gated calcium currents, and it wasnot mimicked by ATPA, suggesting that the GLUK5 subunitdid not contribute (see alsoMulle et al., 2000). The actionof kainate was blocked by CNQX (50�M) but was not


affected by GYKI53655 (30�M) or by a combination of themGluR antagonists MCPG (500�M) plus MSOP (100�M).Cossart et al. (2001)used minimal extracellular stimulationto evoke IPSCs in interneurons and observed that kainate(250 nM) application produced a significant reduction inthe proportion of failures in every cell tested. In contrast,IPSCs evoked in CA1 pyramidal neurons displayed muchgreater heterogeneity in their response to kainate (250 nM)superfusion, with some cells (2/8) showing a significantincrease, some cells (2/8) showing a decrease in IPSC fail-ures and some cells (4/8) showing no change.Jiang et al.(2001)used paired recordings from interneurons and CA1pyramidal cells to study the effect of kainate and endoge-nous glutamate on the success rate of unitary evoked IPSCs.Probability of release was low in approximately half of thepairs and exposure to 300 nM kainate, or release of endoge-nous glutamate via conditioning stimulus trains to excitatoryfibers, caused a significant increase in transmission for thesepairs. Kainate had little effect on pairs with a high initialprobability of transmission; however, exposure to 10�MCNQX, but not 50�M GYKI53655 or SYM2206, causeda reduction in success rate for these pairs, suggesting thatactivation of kainate receptors by ambient glutamate waspartly responsible for the high success rate at these synapses(Jiang et al., 2001). Finally,Semyanov and Kullmann (2001)recorded from interneurons and observed an increase in theamplitude of spontaneous IPSCs during exposure to 1�Mkainate, which they attributed to multiquantal release.

In addition to the extensive work that has been done onCA1 interneurons,Behr et al. (2002)have recently com-pared presynaptic effects of kainate receptor activation oninhibitory transmission in the dentate gyrus of control andkindled rats. In slices from control rats, application of glu-tamate (100�M) or kainate (10�M) in the presence ofSYM2206 (100�M) and D-APV (60�M) increased thefrequency of TTX-sensitive spontaneous IPSCs recordedin dentate granule neurons but reduced the amplitude ofevoked IPSCs and the frequency of TTX-resistant mIPSCs.In tissue from kindled rats, which displayed a higher rest-ing frequency of spontaneous IPSCs, activation of kainatereceptors decreased all three parameters: sIPSC frequency,eIPSC amplitude and mIPSC frequency. The GABAB re-ceptor antagonist CGP55845A (2�M) had no effect ondepression of eIPSCs by kainate, suggesting that feedbackof spontaneously released GABA onto presynaptic GABABreceptors was not required (Behr et al., 2002).

3.1.2. Postsynaptic receptorsIn addition to presynaptic kainate receptors that may

modulate transmitter release, some cells also express post-synaptic kainate receptors that can directly mediate excita-tory transmission. Two studies published together in 1997(Vignes and Collingridge, 1997; Castillo et al., 1997) de-scribed the activation of postsynaptic kainate receptors atmossy fiber synapses onto CA3 neurons in rat and guineapig. After blockade of transmission mediated by AMPA and

NMDA receptors, both groups observed a residual EPSCwhen mossy fibers were stimulated repetitively, but not whensimilar stimuli were delivered to associational/commissuralinputs to CA3 cells. The residual EPSC was attributed tokainate receptors (Vignes and Collingridge, 1997; Castilloet al., 1997) because it was blocked by 10–50�M CNQXbut was unaffected by cyclothiazide (100�M) or by antago-nists of metabotropic glutamate receptors (1.5 mM MCPG),nicotinic cholinergic receptors (10 nM methyllycaconitine),or the ATP receptor antagonist suramin (30�M). Additionalpharmacological analysis (Vignes et al., 1997; Bortolottoet al., 1999) indicated that three different GLUK5-selectiveantagonists, LY293558, LY294486 and LY382884, reducedthe amplitude of the kainate receptor-mediated EPSCsrecorded in CA3 neurons. These results are consistent withthe possibility that the postsynaptic receptors at mossy fibersynapses include a GLUK5 subunit (Vignes et al., 1997);however, this interpretation does not fit well with the ex-pression pattern for GLUK5 mRNA (Paternain et al., 2000)or with recent results in GLUK5-deficient mice, which arediscussed inSection 3.1.3. In addition, more recent pharma-cological studies with the most selective GLUK5 antagonist,LY382884, indicate that at mossy fiber synapses this com-pound only affects presynaptic kainate receptors on mossyfiber terminals and does not block postsynaptic receptorson the CA3 pyramidal cells (Lauri et al., 2001a). The lackof postsynaptic blockade by LY382884 argues against acontribution of GLUK5 to these receptors.

The kainate receptor-mediated EPSC at mossy fibersynapses had a relatively linear current–voltage relation,suggesting that the (Q/R) sites in the channel pore wereedited. Both the rise and decay times for the kainatereceptor-mediated EPSCs were slower than for the AMPAreceptor-mediated component of transmission. This featurehas been observed at other excitatory synapses (Kidd andIsaac, 1999; Li et al., 1999; Bureau et al., 2000) but isnot well explained. Superfusion with blockers of glutamateuptake, such as 100–500�M trans-PDC, did not alter thekinetics of the kainate receptor-mediated EPSCs (Vignesand Collingridge, 1997; Castillo et al., 1997), which sug-gests that their slow kinetics does not depend on glutamatediffusion to an extrasynaptic location.

As mentioned above, postsynaptic kainate receptorsalso contribute to the EPSCs received by CA1 interneu-rons (Frerking et al., 1998; Cossart et al., 1998). Here aswell, the rise and decay times were slower and the peakamplitude was smaller for the kainate receptor-mediatedcomponent of the EPSC than for the component medi-ated by AMPA receptors. Total charge transfer via the twocomponents was similar, however, owing to the slower de-cay of kainate receptor-mediated EPSCs.Frerking et al.(1998) observed no significant difference between thesetwo components of transmission in the quantity 1/CV2, sug-gesting that a similar number of release events contribute toeach component, and predicting that mEPSCs mediated bykainate receptors would be slower and smaller in amplitude


than for AMPA receptor mEPSCs. Subsequent work hasconfirmed this difference in hippocampus (Cossart et al.,2002) and cortex (see below,Kidd and Isaac, 1999) byanalysis of spontaneous miniature synaptic currents. Inhippocampal CA3 pyramidal neurons and CA1 interneu-rons,Cossart et al. (2002)recorded mEPSCs mediated byAMPA receptors only, and mEPSCs involving only kainatereceptors, as well as mixed mEPSCs that included pharma-cologically separable components mediated by AMPA andkainate receptors. In both CA3 pyramidal cells and CA1 in-terneurons, the mEPSCs mediated by kainate receptors hada smaller peak amplitude and slower kinetics than AMPAreceptor mEPSCs, but the overall charge transfer was com-parable for the two components. Comparison of pyramidalcells with interneurons indicated faster kinetics in the in-terneurons for both AMPA and kainate receptor-mediatedcomponents of transmission (Cossart et al., 2002). In thecase of interneurons (Cossart et al., 2002), the decay timeconstant for kainate receptor-mediated EPSCs (∼10 ms)was comparable to deactivation rates for agonist-gated cur-rents, whereas in pyramidal cells the time constant of decaywas much slower (∼90 ms).

Frerking and Ohliger-Frerking (2002)have consideredthe functional implications resulting from the slower kinet-ics for kainate receptor-mediated synaptic currents relativeto EPSCs mediated by AMPA receptors. Not surprisingly,their analysis and subsequent modeling of EPSCs in CA1interneurons (Frerking and Ohliger-Frerking, 2002) suggestthat the kainate receptor-mediated component of synapticcurrent contributes a substantial tonic depolarization overa broad range of physiological firing frequencies, whereasAMPA receptors subserve phasic or transient excitation.Such considerations are likely to apply at other synapseswhere kainate receptors mediate components of synapticcurrent that are relatively slower in their rise and decay ki-netics than the EPSCs mediated by AMPA receptors (Kiddand Isaac, 1999; Li et al., 1999; Bureau et al., 2000; Castilloet al., 1997; Vignes and Collingridge, 1997; Cossart et al.,2001).

In contrast to CA1 interneurons, CA1 pyramidal cells donot exhibit a detectable component of excitatory postsynap-tic current that is mediated by kainate receptors, althoughapplication of exogenous kainate receptor agonists doesevoke kainate receptor-mediated current in CA1 pyrami-dal cells (Chittajallu et al., 1996; Bureau et al., 1999). Inaddition, exposure to low doses of kainate was shown toinhibit postspike potassium current that underlies the slowafterhyperpolarization (IsAHP) in CA1 pyramids (Melyanet al., 2002). This action of kainate was mimicked bydomoate (200 nM) but not ATPA (2�M) or the AMPAreceptor-selective agonist (S)-5-fluorowillardine (300 nM);it was blocked by CNQX (20�M) but not by GYKI52466(100�M). Further analysis suggested a metabotropic ba-sis for this modulation. Treatment withN-ethylmaleimideor the PKC inhibitor calphostin C prevented the action ofkainate onIsAHP. The effect of kainate was not prevented

by blockers for a variety of ionotropic and metabotropicreceptors, suggesting a direct metabotropic action medi-ated by kainate receptors. Blockers that were tested includeantagonists of conventional mGluRs (1 mM MCPG and250�M MSOP), GABA (100�M picrotoxin and 200�M2-OH-saclofen), muscarinic (1�M atropine), opioid (10�Mnaloxone), cannabinoid (2�M AM 251) and adenosine(0.1�M DPCPX) receptors (Melyan et al., 2002).

3.1.3. Transgenic miceTo address the function of specific kainate receptor sub-

units, Heinemann and coworkers (Mulle et al., 1998; Mulleet al., 2000; Contractor et al., 2003) have generated lines ofmice in which genes for individual subunits have been dis-rupted by homologous recombination. All of the mice lack-ing individual subunits are viable. Although the propertiesof these mice have not yet been exhaustively assessed, eventhe initial characterization of their phenotypes has yieldedinteresting insights into the makeup of CNS kainate recep-tors. Interpretation of experiments on knockout animals iscomplicated by the possibility of developmental compensa-tion; however, studies published to date provide little evi-dence for compensatory changes in expression levels of theremaining kainate receptor subunits.

The first knockout study (Mulle et al., 1998) describedthe properties of mice lacking GLUK6. Autoradiography for[3H]kainate binding (Mulle et al., 1998) revealed that theGLUK6-deficient animals lacked the high affinity labelingin hippocampal area CA3 that is prominent in wild-typeanimals (Monaghan and Cotman, 1982). Physiologicalrecordings in slices from knockout animals showed thatthe potency of kainate for activation of whole-cell currentin CA3 neurons was reduced by at least 10-fold relativeto wild-type (change in threshold dose from 1 to 10�M).Moreover, CA3 neurons from GLUK6-deficient animals didnot exhibit kainate receptor-mediated EPSCs when mossyfibers were stimulated in GYKI53655. Subsequent analysisof area CA1 in GLUK6-deficient mice revealed a loss ofwhole-cell currents mediated by kainate receptors in pyrami-dal cells (Bureau et al., 1999). Currents mediated by kainatereceptors in area CA1 interneurons were not eliminated,however, which supports a role for GLUK5 in interneuronalkainate receptors. Depolarization of interneurons mediatedby kainate receptors evoked spontaneous firing of actionpotentials and produced spontaneous inhibitory synapticpotentials that were recorded in pyramidal cells in boththe wild-type and GLUK6 knockout mice (Bureau et al.,1999). A more recent study (Mulle et al., 2000) on GLUK5knockout mice and GLUK5/GLUK6 double knockouts hasshown that both GLUK5 and GLUK6 contribute to kainatereceptors in some CA1 interneurons.

Overall, the GLUK6 knockout mice showed relativelynormal behavior, including comparable learning ability towild-type animals in a water maze test (Mulle et al., 1998).When challenged with interperitoneal kainate injections,however, the knockout mice displayed a higher seizure


threshold and significantly less histological evidence of ex-citotoxic damage to CA3 neurons, which are known to beparticularly vulnerable to kainate toxicity in normal animals(Nadler et al., 1978). Collectively, these results suggest thatproduction of functional kainate receptors in CA3 pyrami-dal cells, as well as CA1 pyramidal neurons, is absolutelydependent on expression of the GLUK6 subunit.

More recent work (Contractor et al., 2000, 2001) hasused knockout mice to evaluate the roles of GLUK5and GLUK6 in presynaptic modulation of inputs to CA3hippocampal neurons. In agreement with earlier studies(Chittajallu et al., 1996; Kamiya and Ozawa, 1998; Schmitzet al., 2000), Contractor et al. (2000, 2001)observed areduction of synaptic transmission by mossy fibers andassociational/commissural fibers during superfusion with3�M kainate. This inhibition by kainate was preserved inGLUK5-deficient animals but was absent in GLUK6 knock-out mice or in GLUK5/GLUK6 double knockouts. Theseresults are in agreement with anatomical studies (Bureauet al., 1999; Paternain et al., 2000) showing low expressionof GLUK5 in dentate granule cells and CA3 pyramidal cellsby in situ hybridization, but they are at odds with the workon GLUK5-selective drugs, described above (Vignes et al.,1998; Bortolotto et al., 1999; Lauri et al., 2001a), which sug-gested that the presynaptic kainate receptor on mossy fiberterminals included a GLUK5 subunit. Either the granule cellsproduce heteromeric receptors that lack the GLUK5 subunit,but which are nevertheless sensitive to GLUK5-selectivedecahydroisoquinoline antagonists, or the neurons actuallyproduce sufficient GLUK5 subunits to render their receptorssensitive to these drugs, but the cells fail to produce func-tional homomeric GLUK5 receptors in animals that lackGLUK6 (Huettner, 2001; Lauri et al., 2003). For example,it could be imagined that GLUK5 splice variants whichfunction poorly on their own (Sommer et al., 1992) mightstill contribute to heteromeric receptors in combinationwith GLUK6. Alternatively, GLUK6 might be required forthe correct subcellular delivery of heteromeric receptors topresynaptic terminals (Huettner, 2001). Direct experimentswith GLUK5-selective compounds on knockout animalsshould eventually resolve these different possibilities.

Contractor et al. (2000)also examined the effect of 3�Mkainate on mini frequency in CA3 pyramidal neurons andon transmission to these cells by perforant path inputs. Ear-lier work by Castillo et al. (1997)in guinea pig CA3 cellsreported no change in mEPSC frequency with kainate ap-plications (0.3 to 3�M); however,Contractor et al. (2000)observed a significant increase in the frequency of mEPSCsin both wild-type and GLUK6-deficient mice. Interestingly,such an increase was not obtained in GLUK5-deficientanimals. Moreover, superfusion of 200�M cadmium wasable to block the increase produced by kainate in wild-typemice, suggesting a possible role for voltage-gated calciumchannels in the effect on mini frequency. With Cd present,3�M kainate actually reduced the frequency of minis inwild-type and GLUK5-deficient animals, but not in GLUK6

knockouts or GLUK5/GLUK6 double knockouts. Kainatealso had a complex effect on transmission by perforantpath inputs (Contractor et al., 2000). In wild-type micekainate potentiated these inputs whereas in slices fromGLUK6-deficient, and some GLUK5-deficient, animals theamplitude of evoked synaptic currents was reduced bykainate. A slight potentiation by kainate was preserved insome of the GLUK5-deficient animals, but kainate had no ef-fect on perforant path transmission in the double knockouts.

Knockout mice have also been used to analyze the roleof the GLUK2 subunit at mossy fiber synapses (Contractoret al., 2003). In contrast to GLUK6, which is required forboth pre and postsynaptic receptors at this synapse (Mulleet al., 1998; Contractor et al., 2000), deletion of GLUK2left presynaptic and postsynaptic kainate receptors in placebut altered their function (Contractor et al., 2003). Postsy-naptic kainate receptors mediated a component of evokedmossy fiber EPSCs in GLUK2 knockout slices, but witha faster rate of decay than was observed in cells fromwild-type animals. Reductions in transmission attributed toactivation of presynaptic kainate receptors persisted in theGLUK2-deficient mice; however the potentiation of trans-mission by low doses of kainate or by the heterosynapticrelease of glutamate was absent from the GLUK2 knockoutslices. Contractor et al. (2003)suggest that all of thesechanges would be consistent with a reduction in the affinityof kainate receptors upon deletion of GLUK2. Interestingly,the GLUK2 knockout slices showed no significant deficitsin mossy fiber homosynaptic frequency facilitation or LTP(Contractor et al., 2003), both of which involve activationof presynaptic kainate receptors (Lauri et al., 2001a,b;Contractor et al., 2001; Schmitz et al., 2001a).

In addition to knockout lines, Heinemann and cowork-ers have also used homologous recombination to generateanimals with altered editing at the Q/R sites of GLUK5(Sailer et al., 1999) and GLUK6 (Vissel et al., 2001). Inadult wild-type animals approximately 50% of mRNAs forthe GLUK5 subunit have been edited to encode an arginineresidue at the Q/R site. For the GLUK6 subunit approx-imately 75% of mRNA is edited. For both subunits, thelevel of editing increases during development (Bernard andKhrestchatisky, 1994; Paschen et al., 1997). Sailer et al.(1999)created homozygous mice encoding an R at the Q/Rposition of GLUK5. These mice showed reduced kainatereceptor-mediated current amplitudes in DRG cells butwere surprisingly normal in their overall behavior and intheir susceptibility to kainate-induced seizures. In contrast,Vissel et al. (2001)created homozygous mice in whichediting of the GLUK6 subunit was prevented. These miceappeared normal in a battery of behavioral tests; however,their susceptibility to kainate-induced seizures was signifi-cantly increased relative to wild-type. Studies of hippocam-pal neurons in vitro demonstrated more robust elevation ofcytosolic calcium upon exposure to kainate in cells lack-ing GLUK6(R). In addition, NMDA receptor-independentLTP could be induced at the medial perforant path synapse


onto dentate granule cells of GLUK6(Q) mice but not inwild-type.

3.1.4. Synaptic plasticityStudies of transmission onto CA3 neurons provided the

first direct evidence that kainate receptors may contribute tosynaptic plasticity (Bortolotto et al., 1999). Previous work(Harris and Cotman, 1986; Zalutsky and Nicoll, 1990) hadshown that associational/commissural fiber inputs to CA3neurons exhibit conventional NMDA receptor-dependentLTP, whereas LTP of mossy fiber inputs is not sensitiveto NMDA antagonists. Additional studies (Castillo et al.,1994; Ito and Sugiyama, 1991) suggested that blockadeof non-NMDA receptors with the broad-spectrum antago-nists CNQX or kynurenic acid did not prevent induction ofmossy fiber LTP; however,Bortolotto et al. (1999)foundthat high doses of these antagonists (10 mM kynurenic acidor 10�M CNQX), as well as the GLUK5-selective antag-onist LY382884 (10�M), were capable of blocking LTPinduction at mossy fiber synapses under their recordingconditions. In contrast, LY382884 had no effect on LTPinduction at associational/commissural synapses onto CA3cells (Bortolotto et al., 1999). There has been disagree-ment over the dose-dependence of LTP-induction blockadeby non-NMDA receptors antagonists (Nicoll et al., 2000;Bortolotto et al., 2000; Schmitz et al., 2001b), but it isgenerally agreed (Schmitz et al., 2001a; Contractor et al.,2001; Lauri et al., 2001a,b) that presynaptic kainate re-ceptors mediate a significant component of short-termfrequency-dependent facilitation of mossy fiber transmis-sion (see above,Section 3.1.1.1). Lauri et al. (2001a)pro-vided evidence that activation of these presynaptic kainatereceptors was required for the induction of mossy fiber LTP,and that establishment of LTP occluded the facilitation thatwas sensitive to kainate receptor antagonists (Lauri et al.,2001a; Ji and Staubli, 2002).

More recently, Lauri et al. (2003) have implicatedcalcium-induced calcium release from intracellular storesas an important component of mossy fiber LTP. Their re-sults (Lauri et al., 2003) suggest that the necessary triggerfor release from internal stores can be provided by calciumentry either through calcium-permeable kainate receptors orthrough voltage-gated calcium channels, with entry throughvoltage-gated channels being the dominant factor whenextracellular calcium levels are high (∼4 mM). This studyhelps to resolve earlier disagreements over the ability ofkainate receptor antagonists to block LTP induction at thissynapse (Nicoll et al., 2000; Bortolotto et al., 2000), be-cause experiments that appeared to be in conflict were per-formed under different ambient calcium levels. Additionalevidence supporting a role for kainate receptors in mossyfiber LTP induction has come from analysis of knock-out mice (Contractor et al., 2001). This work (Contractoret al., 2001), however, indicated a requirement for theGLUK6 subunit. Mossy fiber LTP was normal in slicestaken from GLUK5 knockout mice but significantly reduced

in GLUK6-deficient tissue as compared to wild-type. Toexplain the ability of GLUK5-selective antagonists to blockmossy fiber LTP,Lauri et al. (2003)propose that dentategranule cells normally express heteromeric kainate recep-tors that include both the GLUK5 and GLUK6 subunits;functional receptors continue to be expressed in animalslacking GLUK5, but not when GLUK6 is deleted.

3.2. Cortex

Kidd and Isaac (1999)have demonstrated a contribu-tion by postsynaptic kainate receptors to thalamocorticaltransmission. Their results, obtained in slices from 3- to8-day-old rats, indicate that kainate receptors are presentat these synapses early in development. They recordedfrom layer IV neurons in primary somatosensory cortex.In most cases, evoked EPSCs displayed a component me-diated by AMPA and by kainate receptors, although someexamples of AMPA- and kainate-only evoked EPSCs wereobserved. Analysis of spontaneous synaptic events revealedtwo distinct populations: one with a fast decay typical ofAMPA receptors and the other with a much slower de-cay rate, which matched the slow decay of evoked kainatereceptor-mediated synaptic currents. The slow kinetics ofevents mediated by kainate receptors apparently does notarise from the slow diffusion of transmitter from sites ofrelease. Manipulations designed to alter glutamate uptake,including temperature elevation and incubation with trans-porter antagonists, produced equivalent effects on AMPAand kainate receptor-mediated components (Kidd and Isaac,2001). Collectively, these results suggest that kainate re-ceptors and AMPA receptors may be segregated to distinctsynaptic contacts and that the AMPA receptors progressivelyreplace kainate receptors during the course of development.Induction of LTP by a pairing protocol led to a reductionin the component of transmission mediated by kainate re-ceptors, coupled with a significant increase in the AMPAreceptor-mediated component (Kidd and Isaac, 1999).

In addition to postsynaptic kainate receptors, some tha-lamocortical synapses may exhibit presynaptic kainate re-ceptors that modulate release.Kidd et al. (2002)tested forpresynaptic modulation by kainate receptor agonists at tha-lamic inputs to barrel cortex. In slices from early postnatalrats (P3 to P5) repeated stimulation of thalamocortical inputsat frequencies ranging from 10 to 100 Hz caused significantdepression of EPSCs recorded in layer IV neurons. Exposureto ATPA produced a similar reduction in EPSC amplitude.Application of LY382884 (10�M) reduced the depressionobserved at high frequencies (50 and 100 Hz), but causedminimal change at lower frequencies, leadingKidd et al.(2002)to propose two components of depression: a rapidlydecaying component, mediated by kainate receptors, thatwas only apparent with high frequency stimulation, and aslower component of depression that did not involve kainatereceptors. Interestingly, the kainate receptor-mediated presy-naptic modulation was not detected in slices from slightly


older animals (P7 to P8), suggesting a developmental changein sensory processing that involves a change in kainate re-ceptor expression or properties (Kidd et al., 2002).

Evidence for presynaptic kainate receptors has also beenobtained (Ali et al., 2001) at synapses formed by inhibitoryinterneurons onto layer V pyramidal cells in rat motor cor-tex (P17 to P22). Paired recordings demonstrated a reduc-tion in evoked IPSCs during exposure to ATPA (1�M) orglutamate (10�M). This action was inhibited by 30�MCNQX, but was not blocked by GYKI53655 (50�M) or byinhibitors of mGluRs (1 mM MCPG and 100�M CPPG),GABAB (100�M CPG 55845), opioid (100�M naloxone),muscarinic (50�M atropine), and adenosine (1�M DPCPX)receptors (Ali et al., 2001). Changes in the failure rate andcoefficient of variation produced by kainate receptor ac-tivation were consistent with a presynaptic change in re-lease. Interestingly, depolarization of the postsynaptic cellto −40 mV for 1.5 s produced a CNQX-sensitive reductionin evoked IPSCs thatAli et al. (2001)attributed to dendriticrelease of glutamate and subsequent activation of presynap-tic kainate receptors.

3.3. Amygdala

Li and Rogawski (1998)have reported on synaptic trans-mission mediated by kainate receptors in the basolateralamygdala. They used intracellular electrodes to record fromcells in acute slices. EPSPs were evoked by stimulation ofeither the external capsule or the basal amygdala. Superfu-sion with 50�M GYKI52466 or 53655 completely blockedresponses to basal amygdala stimulation, but caused onlypartial blockade of EPSPs evoked by external capsule stim-ulation. The residual EPSP displayed temporal summationduring brief 50 Hz trains. It was blocked almost completelyby addition of 20�M CNQX, 10�M LY293558, or 20�MLY377770 to the bath (Li and Rogawski, 1998; Li et al.,2001). Subsequent work byLi et al. (2001)has demonstratedinvolvement of kainate receptors in homosynaptic and het-erosynaptic potentiation of transmission in the amygdala. Incontrast to studies of LTP in the hippocampus, which nor-mally elicit potentiation with brief high-frequency stimulustrains, Li et al. (2001)observed progressive enhancementof transmission during prolonged (15 min) low frequency(1 Hz) stimulation. Potentiation was blocked by antagonistswith selectivity for the GLUK5 subunit of kainate receptors(LY377770 and LY382884) but not by antagonists to NMDA(100�M APV), AMPA (50 �M GYKI53655) or groupI metabotropic (20�M CPCCOEt) glutamate receptors.Potentiation was mimicked by brief (10min) superfusionwith the GLUK5-selective agonist ATPA (20�M) and wasblocked by calcium-free medium or by pre-equilibrationwith the cell-permeable chelator BAPTA-AM. In addition,both the NMDA and AMPA receptor-mediated componentsof transmission were potentiated, suggesting a presynap-tic change in glutamate release. Interestingly, potentiationwas not restricted to the fibers stimulated during the induc-

tion period (homosynaptic potentiation), but instead wasgeneralized to other inputs (heterosynaptic potentiation),including inputs from the basal amygdala (Li et al., 2001).

Inhibitory transmission in the amygdala is also subject toregulation by kainate receptors.Braga et al. (2003)recordedevoked IPSCs from pyramidal cells in the basolateral amyg-dala, observing a reduction in failures with exposure tolow doses of ATPA (300 nM) or glutamate (5�M), and anincrease in failures with higher agonist doses (1–10�MATPA, 30–200�M glutamate). These effects were recordedin the chronic presence of APV (50�M), GYKI53655(50�M), SCH50911 (20�M) and CPCCOEt (30�M) toblock NMDA, AMPA, GABAB and group I mGluRs. Asimilar bi-directional modulation was also observed formIPSCs recorded in the presence of TTX; 300 nM ATPAenhanced mIPSC frequency, whereas higher doses reducedthe frequency (Braga et al., 2003). Effects of ATPA andglutamate were blocked by LY293558. Moreover, exposureto this antagonist reduced evoked IPSC amplitude and in-creased failures, suggesting that endogenous glutamate mayprovide tonic activation of kainate receptors in the sliceunder control conditions (Braga et al., 2003).

3.4. Retina

In the ground squirrel retina (DeVries and Schwartz,1999; DeVries, 2000), kainate receptors mediate transmis-sion between cone photoreceptors and specific classes of“off” bipolar cells. Using paired recordings from cones andbipolar cells,DeVries and Schwartz (1999)observed thatstep depolarization of the cone from−70 to 0 mV evoked atransient excitatory current in the postsynaptic bipolar cell.This synaptic response was blocked by CNQX (30�M),but was insensitive to GYKI53655 (25�M), cyclothiazide(200�M) and APV. During prolonged depolarizations, thesynaptic current decayed rapidly (τ ∼ 5 ms) to reach asteady state level that was less than 5% of the initial peakamplitude. Similar desensitizing currents were observedwhen glutamate was applied rapidly to isolated bipolar cells.Strong desensitization to glutamate is typical of kainatereceptors, and may help to reduce the cost and maintainthe sensitivity of tonic signaling at this synapse. Bothrod and cone photoreceptors are depolarized in the dark,causing ongoing release of transmitter onto second-ordercells. Exposure to light produces a graded hyperpolariza-tion of photoreceptors and a decrease in transmitter re-lease. Because of the high input resistance of bipolar cells(∼1 G�), DeVries and Schwartz (1999)note that even therelatively small synaptic currents that are evoked throughdesensitized kainate receptors (approximately−10 pA),when summed over inputs from several cones, will besufficient to drive the bipolar cell membrane potentialthrough its normal 25 mV range of operation. Moreover,the properties of kainate receptor desensitization will en-sure that postsynaptic responses in off-bipolar cells willbe greatest for abrupt reductions in light intensity follow-


ing a prolonged exposure to light (DeVries and Schwartz,1999).

In subsequent work,DeVries (2000)showed that two dif-ferent morphologically identified subtypes of off bipolarscells, b3 and b7 cells, exhibited kainate receptors with dis-tinct physiological properties. In both cell types kainate re-ceptors were activated by ATPA, suggesting a contributionby the GLUK5 subunit; however, the b3 class of off bipolarsexpressed kainate receptors with slow recovery from desen-sitization to glutamate (t1/2 ∼ 1 s), whereas b7 bipolar cellsrecovered from desensitization more quickly (t1/2 ∼ 0.2 s).Transmission from cones onto a third type of off bipolar cell(b2) was found to be mediated by AMPA receptors (DeVries,2000).

3.5. Striatum

Kainate receptor subunit expression (Bischoff et al., 1997;Bahn et al., 1994) and kainate binding (Monaghan andCotman, 1982) are prominent in the striatum. The majorityof projection cells express GLUK6 (Chergui et al., 2000).An early study (Calabresi et al., 1990) observed responsesto kainate at submicromolar concentrations that are likely tohave been selective for kainate receptors. More recent work(Chergui et al., 2000) with AMPA-selective antagonistsand GLUK6-deficient mice has confirmed the expression offunctional kainate receptors by cells in slices of striatum. Noevidence has been obtained for kainate receptor-mediatedexcitatory postsynaptic currents in striatal cells (Cherguiet al., 2000); however, modulation of GABAergic trans-mission was observed upon activation of kainate receptorswith exogenous agonist. During superfusion with kainatereceptor agonists, IPSCs evoked by local stimulation werereduced in amplitude (Chergui et al., 2000). Althoughkainate receptor agonists elicited depolarization and firingof action potentials in striatal cells, these effects did notappear to directly underlie the change in evoked GABAer-gic transmission. Instead, much of the reduction in evokedtransmission could be prevented by adenosine A2A receptorantagonists, suggesting that exposure to kainate stimulatedthe release of an endogenous agonist for these receptorsfrom within the slice (Chergui et al., 2000).

Two studies have examined kainate receptors in the ven-tral striatum or nucleus accumbens (Crowder and Weiner,2002; Casassus and Mulle, 2002). As discussed above fordorsal striatum, most neurons in the nucleus accumbenspossessed functional kainate receptors that depended on ex-pression of the GLUK6 subunit (Casassus and Mulle, 2002).No evidence was obtained for a contribution by postsynap-tic kainate receptors at excitatory synapses (Crowder andWeiner, 2002; Casassus and Mulle, 2002); however, excita-tory inputs to accumbens neurons were inhibited by exposureto low concentrations of kainate (0.3–1�M). This declinein excitatory transmission was associated with a reductionin 1/CV2 (Casassus and Mulle, 2002) and an increase inpaired-pulse facilitation (Crowder and Weiner, 2002), which

is consistent with a presynaptic decrease in release probabil-ity. In this case, the effects of kainate were not prevented bymetabotropic glutamate receptor antagonists (1 mM MCPGplus 100�M CPPG), or by GABAB (20�M SCH50911)or adenosine (200�M theophylline) receptor antagonists(Crowder and Weiner, 2002). Modulation of excitatorytransmission was preserved in single knockouts of eitherGLUK5 or GLUK6, but was eliminated in double knockoutsof both GLUK5 and GLUK6 (Casassus and Mulle, 2002).

3.6. Hypothalamus

In a study of rat hypothalamic neuronsLiu et al. (1999)observed an increase in spontaneous IPSC frequency dur-ing superfusion with kainate. Recordings from hypothala-mic neurons in acute tissue slices revealed a 50% increasein IPSC frequency during perfusion with 1�M kainate plusAPV (50�M) and GYKI52466 (100�M). In cultured hy-pothalamic neurons 10�M kainate caused a similar 50% in-crease in the frequency, but no change in the amplitude, ofmIPSCs recorded in the presence of TTX and GYKI52466,suggesting a presynaptic site of action. Kainate also causeda 7–40 pA increase in the holding current at−70 mV andenhanced the frequency of spontaneous evoked IPSCs inthe absence of TTX, indicating the likely presence of soma-todendritic kainate receptors in these neurons as well (Liuet al., 1999).

3.7. Cerebellum

A variety of cell types within the cerebellum expresskainate receptors, with each cell type showing a distinct pat-tern of subunit expression. Purkinje cells express the GLUK5and GLUK1 subunits (Wisden and Seeburg, 1993). Kainatereceptor-mediated currents have been recorded in Purkinjecells (Renard et al., 1995; Brickley et al., 1999), although thefunction of these receptors remains obscure. Granule cellsexpress GLUK5, GLUK6 and GLUK2 even before they mi-grate to their final destination in the internal granule layerbetween postnatal days 7–14 (Belcher and Howe, 1997;Pemberton et al., 1998). Analysis of granule cell mRNAby RT-PCR (Belcher and Howe, 1997) indicates that at allstages the Q/R site of GLUK5 is largely unedited, whereasthat of GLUK6 is predominantly in the edited form. Overall,the level of editing increases during postnatal development,as does expression of the major enzymes responsible forediting. Premigratory granule cells in the external granulelayer exhibit kainate receptor-mediated currents followingexposure to Con A, but currents mediated by AMPA recep-tors were small or absent at this stage (Smith et al., 1999).More mature cells in the internal granule layer express bothkainate and AMPA receptors.

A recent paper byDelaney and Jahr (2002)providesevidence for presynaptic kainate receptors at granule cellsynapses onto Purkinje cells and stellate cells. In bothcases, activation of these presynaptic receptors by low doses


of exogenous agonist (5 nM domoate), or low frequencystimulation (10–20 Hz), resulted in facilitation of release.Higher agonist doses (10–500 nM domoate) or higherfrequency stimulation (100 Hz) produced synaptic depres-sion at synapses onto stellate cells. In contrast, kainatereceptor-mediated facilitation of parallel fiber to Purkinjecell synapses was observed at all stimulus frequencies tested(up to 100 Hz) and for exposure to 50 nM domoate; 500 nMdomoate produced depression of granule cell to Purkinjecell synapses.

Both GLUK5 and GLUK6, but not GLUK7 or GLUK1 orGLUK2, have been detected in cerebellar Golgi cells (Bureauet al., 2000), which are interneurons with cell bodies inthe granule cell layer. Kainate application evokes current inthese cells and kainate receptors mediate a component ofexcitatory postsynaptic current produced by stimulation ofparallel fibers. Both the agonist-evoked and synaptic currentsare absent in GLUK6 knockout mice (Bureau et al., 2000).

3.8. Spinal cord

Kainate receptor expression is not particularly prominentin the spinal cord, as judged by in situ hybridization (Tölleet al., 1993) or immunocytochemistry (Petralia et al., 1994);however, several studies have provided physiological evi-dence for functional kainate receptors in spinal neurons (Liet al., 1999; Kerchner et al., 2001a; Wilding and Huettner,2001). As in the hippocampus, primary afferent synapsesin the dorsal horn of the spinal cord may represent an ex-ample where both pre and postsynaptic kainate receptorsmay play a role in transmission at individual contacts. Evi-dence for postsynaptic kainate receptors was obtained byLiet al. (1999)in studies of rat spinal cord slices. Whole-cellrecording in layer II of the dorsal horn revealed a slow com-ponent of primary afferent transmission that was insensi-tive to 100�M GYKI53655 or SYM2206, but was inhibitedby 10�M CNQX and by selective desensitization with 1to 5�M SYM2081. This kainate receptor-mediated compo-nent of transmission was most pronounced for stimulationintensities that were sufficient to activate high threshold Adelta and C fibers. Lower intensity stimulation evoked EP-SCs that were entirely mediated by AMPA receptors. In con-trast to the hippocampus and amygdala, however, kainatereceptor-mediated EPSCs in the dorsal horn showed depres-sion during brief stimulation trains. Exposure to Con A re-duced the extent of depression, which suggests that it mayinvolve the desensitization of postsynaptic kainate receptors.

More recent work (Kerchner et al., 2001b) has providedevidence for expression of presynaptic kainate receptorsby spinal cord inhibitory interneurons. In the presence ofTTX, application of kainate (10�M) or glutamate (30�M)to cultured rat dorsal horn neurons increased the frequencyof mIPSCs by 8–10-fold, suggesting a direct action onpresynaptic nerve terminals. This elevation of release re-quired extracellular Na+ and Ca2+. It was blocked by thenon-selective calcium channel antagonist Cd2+ (50�M)

and partially prevented by�-conotoxin GVIA (0.5�M) andMVIIC (0.5 �M), which are inhibitors of N and P/Q typecalcium channels. These properties suggest a mechanisminvolving depolarization of presynaptic terminals leadingto calcium entry through voltage-gated channels. Althoughkainate increased mIPSC frequency, under most conditionsexposure to kainate caused a net reduction of evoked trans-mitter release. This effect on evoked inhibitory transmissionwas mimicked and occluded by the GABAB receptor agonistbaclofen (5�M) and was blocked by the GABAB antago-nist CGP55845 (10�M), suggesting that local elevation ofGABA by an increase in spontaneous quantal release wassufficient to activate presynaptic GABAB receptors and sup-press evoked transmission. Interestingly, the activation ofGABAB receptors had a selective action on evoked release,causing no decrease in mIPSC frequency under resting con-ditions, or when the frequency was elevated by exposureto kainate or KCl (Kerchner et al., 2001b). Recordings inacute spinal slices demonstrated that endogenous glutamate,released upon stimulation of primary afferent fibers, causedsuppression of eIPSCs via activation of kainate receptors.This effect of primary afferent stimulation was blocked byCNQX (20�M) but not SYM2206 (100�M). In addition,it was prevented by the GABAB antagonist CGP55845(10�M), which is consistent with the feedback mechanismdelineated in cell culture (Kerchner et al., 2001b).

3.9. Dorsal root ganglia

Kainate receptors were first described on sensory axons inperipheral nerve. Studies by Evans and coworkers (Davieset al., 1979; Agrawal and Evans, 1986) demonstrated depo-larization of dorsal root fibers by exposure to kainate, whichdisplayed a different pharmacology from the depolarizationof spinal neurons by excitatory amino acids (see alsoLeeet al., 2002). These results ledWatkins and Evans (1981)to propose the existence of a unique class of receptors se-lective for kainate. Further analysis in this system showedthat treatment with kainate also produced selective block-ade of action potential conduction along C-fibers (Agrawaland Evans, 1986), which are the small diameter, high thresh-old afferents that convey nociceptive and thermoreceptiveinformation into the CNS. Subsequent patch-clamp stud-ies (Huettner, 1990; Wong and Mayer, 1993; Lee et al.,2001) on cells isolated from dorsal root ganglia (DRG)confirmed the expression of functional kainate receptorson the small diameter sensory neurons that give rise toC-fibers.

Several studies have attempted to address the role thatDRG cell kainate receptors serve. It has been proposed thatkainate receptors function as presynaptic autoreceptors atprimary afferent synapses in the dorsal horn (Agrawal andEvans, 1986; Hwang et al., 2001). There also is evidence forrouting of kainate receptors to the peripheral axon branch(Agrawal and Evans, 1986; Ault and Hildebrand, 1993;Coggeshall and Carlton, 1998) where they might function


as sensory receptors, detecting glutamate released followingtissue damage.

In a study of cultured DRG cells,Lee et al. (1999)ob-served that application of 100�M kainate evoked actionpotentials that were recorded in the cell body. In record-ings from neurons in lamina II of spinal cord slices, thisstudy showed an increase in spontaneous postsynaptic cur-rents during superfusion with 10�M kainate. More recently,Kerchner et al. (2001a)have shown both in culture and inslices that evoked transmission from DRG cells to spinal dor-sal horn neurons was inhibited by exposure to 10�M kainateor to the GLUK5-selective agonist ATPA (2�M). Kainatereceptors expressed by rat DRG neurons were shown to beselectively desensitized by ATPA (Kerchner et al., 2001a;Wilding and Huettner, 2001), which had little effect on neu-rons from rat dorsal horn. Further analysis of knockout mice(Kerchner et al., 2002) confirmed this differential sensitivityto ATPA, but also provided evidence that both GLUK5 andGLUK6 contribute to the receptors expressed by DRG andspinal neurons.

4. Perspectives

In many regions of the nervous system, the involvement ofpresynaptic and/or postsynaptic kainate receptors in synaptictransmission is now firmly established. Although controver-sies and uncertainties remain, a number of general themeshave emerged. First, activation of kainate receptors producesbi-directional modulation of both excitatory and inhibitorytransmission. Low to moderate activation enhances trans-mission, whereas stronger activation inhibits transmission.Second, synaptic currents mediated by postsynaptic kainatereceptors exhibit lower peak amplitude and slower decaykinetics than AMPA receptor-mediated EPSCs recorded inthe same cell. Total charge delivery by AMPA and kainatereceptor-mediated EPSCs may be comparable.

Third, synaptic kainate receptors may play a strictlyionotropic role, or in some cases may trigger a metabotropiccascade. The mechanistic links between known kainatereceptor subunits and metabotropic effectors have not yetbeen completely defined. Fourth, knockout mice have pro-vided valuable information about the composition of nativereceptors and the function of individual subunits, althoughinterpretation of these studies is complicated by the pos-sibility of compensation. Future experiments will likelyextend the roster of synapses where kainate receptors playa role. In addition, future work should broaden our un-derstanding of the natural activity patterns that best elicitkainate receptor activation by endogenous glutamate andshed more light on the consequences of such activation onthe operation of individual synapses and neuronal networks.

Clinical interest in kainate receptors seems certain to in-crease. There is substantial evidence that these receptors con-tribute to the well-known ability of kainate to elicit seizures(Ben-Ari and Cossart, 2000) and cause excitotoxic cell

death (Nadler et al., 1978). Recent experiments bySmolderset al. (2002)suggest that GLUK5-selective antagonists canblock the induction of seizures by pilocarpine or electri-cal stimulation, as well as suppress pre-established seizureactivity. Another recent study of seizure propagation fromone hippocampus to the contralateral hippocampus foundthat ATPA (1�M) produced a paradoxical anti-epilepticeffect, which was attributed to preferential activation of in-terneurons (Khalilov et al., 2001). In addition, several stud-ies have provided evidence for antinociceptive effects byGLUK5-selective compounds (Procter et al., 1998; Simmonset al., 1998; Stanfa and Dickenson, 1999; Sutton et al., 1999;Mascias et al., 2002), supporting a role for kainate receptorsin pain sensation (Ruscheweyh and Sankuhler, 2002).

Much remains to be learned about the structural basisfor kainate receptor heterogeneity and the mechanisms thatunderlie the metabotropic actions that have been attributedto kainate receptors. In addition, the slow time course ofEPSCs mediated by postsynaptic kainate receptors remainspoorly explained. In a few cases, the time course of decayis comparable to receptor deactivation (Cossart et al., 2002;DeVries and Schwartz, 1999), but in other cells, the EP-SCs decay at a much slower rate. All of the ongoing workon kainate receptors would be aided by the developmentof more potent and more selective antagonists. Compoundsselective for GLUK5 have yielded a great deal of informa-tion (Bleakman et al., 1996b; O’Neill et al., 1998), but thefield still lacks a selective antagonist that blocks GLUK6 orthe other kainate receptor subunits (Bleakman and Lodge,1998). Ever since the pioneering studies by Watkins andcoworkers (Watkins and Evans, 1981), progress in elucidat-ing the function of glutamate receptors has hinged on thediscovery of new pharmacological tools. This trend appearscertain to continue in the case of kainate receptors.

Acknowledgements

I am grateful to the NIH for supporting my research(NS30888) and to Geoff Swanson, Tim Wilding and GeoffKerchner for careful reading of the manuscript.

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