Available online at www.sciencedirect.com

Sensory representations in cerebellar granule cellsAlexander Arenz, Edward F Bracey and Troy W Margrie

Cerebellar granule cells are an attractive model system for

examining synaptic transmission and temporal integration,

because of their small number of excitatory synaptic inputs and

electrotonic compactness. Recent in vivo whole-cell

recordings have revealed how sensory stimuli are represented

by synaptic activity across multiple modalities and cerebellar

regions. By monitoring the activity of individual synapses, the

reliability of these unitary signals has been quantified, and the

complexity of a granule cell’s receptive field has been explored

at the highest resolution. Here we describe the emerging

principles of synaptic sensory representation and their

consequences for information processing in the granule cell

layer.

Address

Department of Neuroscience, Physiology and Pharmacology, University

College London, Rockefeller Building, 21 University Street, WC1E 6DE

London, United Kingdom

Corresponding author: Margrie, Troy W (t.margrie@ucl.ac.uk)

Current Opinion in Neurobiology 2009, 19:445–451

This review comes from a themed issue on

Sensory systems

Edited by Leslie Vosshall and Matteo Carandini

Available online 3rd August 2009

0959-4388/$ – see front matter

# 2009 Elsevier Ltd. All rights reserved.

DOI 10.1016/j.conb.2009.07.003

IntroductionNeurons process information. In order to truly understand

the computations single neurons and subsequently net-

works perform, a full description of all synaptic inputs and

their activity is required. With (on average) only four

excitatory inputs [1,2], the cerebellar granule cell seems

to be an ideal model system to achieve this goal. These

excitatory inputs are provided by mossy fibres (MFs) that

arise from thebrainstem andspinal cord andcarry a plethora

of sensory-motor information to be used for the co-ordina-

tion of movement and the maintenance of balance. Know-

ing how these sensory-motor stimuli are represented and

combined at the level of individual granule cells will there-

fore help our understanding of information processing at

the input layer of the cerebellar cortex.

Long-standing theories of cerebellar operation suggest

that the design of the granule cell layer reflects a function

involving sparsification of the incoming MF signals and

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generation of many thousandfold new patterns of activity

that are learned and stored by the granule cells’ postsyn-

aptic targets, the Purkinje cells [3,4]. Although synaptic

transmission between MFs and granule cells has been

thoroughly characterised in vitro, such theories of granule

cell function have not been directly challenged since the

activity of individual granule cells has been difficult to

isolate and record in vivo. Recently however, in vivowhole-cell recordings have overcome this technical hur-

dle and are beginning to shed light on how these MF

inputs onto granule cells signal sensory stimuli within and

across different modalities and regions of the cerebellum

(Figure 1a). Here we report on data that address several

key questions relating to sensory signalling through these

synapses: firstly, How do patterns of MF synaptic input

reflect the features of a stimulus; secondly, How accu-

rately can individual synapses report such information

and thirdly, What are the emerging principles of granule

cell sensory receptive fields that ultimately determine the

kinds of computations these cells can perform. Knowing

the answers to these questions will reflect a greater un-

derstanding of the function of the cerebellar granule cell.

Anatomy and physiology of the MF–granulecell synapseMFs relay information from the spinal cord, brain stem

nuclei (including the vestibular nuclei), primary vestibular

afferents and the deep cerebellar nuclei [5,6]. They can be

unimodal [7,8] or multimodal [9], and carry proprioceptive

[8,10], somatosensory [11,12��,13�,14��,15�], auditory [16],

vestibular [9,17��], visual [18] and eye movement-related

information [19]. On their course through the white matter

of the cerebellar cortex MFs branch extensively whilst

functionally related inputs converge and reflect a topo-

graphic organisation [20] within the granule cell layer,

where they terminate within specialised structures, termed

glomeruli (Figure 1b). Within the glomerulus, MFs release

glutamate onto the dendrites of granule cells and GABA-

ergic Golgi cells [1,21–23], which provide both feed-for-

ward and feedback inhibitory loops onto granule cells

[1,24–26] (Figure 1b,c). Here we focus on data recorded

from granule cells located in crus I and IIa, the C3 zone of

the paravermis of lobules IV and V, and the flocculus

(Figure 1a), regions that process, primarily, whisker/peri-

oral, forelimb somatosensory and proproceptive, and ves-

tibular (and other motion-related) signals, respectively.

At the MF–granule cell synapse, glutamate binds to

AMPA and NMDA receptors [27,28], though the contri-

bution of the latter to the excitatory postsynaptic current

(EPSC) diminishes with maturation [29]. The structure of

the glomerulus, with its dense packing of dendrites

Current Opinion in Neurobiology 2009, 19:445–451

446 Sensory systems

Figure 1

The mossy fibre to granule cell synapse. (a) Gross anatomy of the cerebellum showing three regions that have received particular experimental focus:

crus I and IIa, the C3 zone of lobules IV and V in the anterior paravermis and the flocculus (cerebellar drawing after [20]). (b) Reduced circuit diagram of

the cerebellar cortex. Granule cells (GCs) at the input stage of the cerebellar cortex receive input from on average four mossy fibres (MFs). The axons

of granule cells project to the molecular layer, where they bifurcate and form parallel fibres that make excitatory synaptic connections onto Purkinje

cells (PCs), the sole output cells of the cerebellar cortex. Golgi cells (GoCs) in the granular layer receive input from MFs and parallel fibres and inhibit

granule cells, thereby implementing feed-forward and feedback inhibitory circuits. (c) Within the glomerulus, one MF terminal (blue) synapses onto the

dendrites of about 50 granule cells (red), as well as onto the dendrites of Golgi cells (green). In addition, Golgi cell axons (yellow) form inhibitory

synaptic contacts onto granule cell dendrites. The glomerulus as a whole is encapsulated in a glial sheath (brown) (drawing after [1]). (d) Glutamate

released onto one granule cell (GC1) can diffuse out of the synaptic cleft and spillover onto AMPA receptors in neighbouring synaptic clefts, where the

same MF terminal connects onto the dendrite of another granule cell (GC2). Usually EPSCs in granule cells arise from a combination of direct release

and spillover transmission (d1). Only when all direct release sites onto that granule cell fail, spillover currents can be seen in isolation (d2). The slow rise

and decay times of the spillover current prolong the decay of the average EPSC. Isolated direct transmission without spillover contribution, observed

under low release probability conditions, is characterised by significantly faster decay times (d3).

(Figure 1c), promotes cross-communication between

synaptic clefts whereby glutamate released at one

synapse can spillover onto AMPA receptors located on

dendrites belonging to other granule cells connected to

the same glomerulus (Figure 1d1–d3) [30,31]. This spil-

lover prolongs the decay of synaptic currents, increasing

the time window of synaptic integration, and is thought to

increase the reliability of transmission.

At this synapse short-term depression has been shown to

occur over EPSC frequencies ranging 1–200 Hz [13�,32].

MFs are able to sustain high rates of transmitter release

because of a large vesicle pool and fast vesicle reloading.

However postsynaptic AMPA receptors desensitize

within a few pulses to a steady state of depression [32],

which has been proposed to be one mechanism that could

ensure linearity of transmission over a range of synaptic

Current Opinion in Neurobiology 2009, 19:445–451

signalling frequencies [17��,33�]. In addition, long-term

potentiation at this synapse can be induced by high-

frequency theta-burst or tetanic electrical stimulation

in vitro. This can last for tens of minutes [34,35] and

may help fine-tune precise spiking in granule cells [36].

Although several groups have explored the dynamics of

synaptic transmission between MFs and granule cells invitro [28,32,37], only recently have whole-cell recordings

made it possible to study the physiology of this synapse in

the intact system [12��,13�,14��,15�,17��].

Patterns of sensory-evoked excitatorysynaptic transmission in granule cellsIn order to understand how these synaptic mechanisms

are employed to signal sensory stimuli, whole-cell record-

ings from granule cells in rats and mice under ketamine

anaesthesia [12��,13�,17��] and in decerebrate cats

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Sensory representations in cerebellar granule cells Arenz, Bracey and Margrie 447

Figure 2

Sensory-evoked excitatory synaptic responses in granule cells. (a)

Whisker deflection and perioral stimulation with an air puff (stim) evokes

short bursts of EPSCs in granule cells in crus I and IIa rat under

ketamine/xylazine anaesthesia [12��], which is believed not to impact on

MF–granule cell transmission [43]. Synaptic currents are shown

schematically (middle) and reflected as a raster plot (beneath). (b) In the

anterior paravermis of the decerebrate cat, electrical and manual

cutaneous stimulation to the forelimb (top) evokes a phasic synaptic

response, whilst joint angle manipulation of the digits of the forepaw

(bottom) evokes sustained synaptic activity [14��]. (c) In the flocculus of

the ketamine/xylazine anaesthetised mouse, graded vestibular

stimulation using horizontal whole-body rotation with a discontinuous

sinusoidal velocity stimulus (top and middle trace) evokes a bidirectional

modulation of the EPSC frequency that correlates with the animal’s

direction and velocity of motion [17��].

[14��,15�] have been performed. Those studies indicate

that the temporal patterning of spontaneous and sensory-

evoked synaptic activity varies widely across cerebellar

regions and sensory modalities (Figure 2). In crus I and IIa

of the rat, spontaneous EPSCs occur at low frequencies of

around 4 Hz [13�]. In contrast, in the C3 zone of lobules

IV and V in the cat spontaneous synaptic input ranges

from 10 to 50 Hz [14��]. Likewise, ongoing MF–granule

cell activity in the flocculus of the mouse ranges from <1

up to 40 Hz [17��]. Since these differences in the rates of

spontaneous activity are observed across functionally

distinct regions of the granule cell layer, they might

reflect how MF–granule cell synapses encode sensory

information unique to that region and modality.

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For example in crus I and IIa of the rat, a whisker

deflection or perioral stimulus (air puff) evokes short

bursts of two to five EPSCs with instantaneous frequen-

cies of up to 700 Hz [12��,13�], which reliably report the

onset of the stimulus (Figure 2a). The low spontaneous

EPSC rates observed in these granule cells might reflect

inputs with low noise, ideally suited to provide maximum

signal to noise ratios for reporting stimulus onset. Sim-

ilarly, cutaneous stimulation of the forepaw of the cat

evokes a phasic synaptic response in C3 granule cells that

exhibit lower spontaneous rates compared to cells

responding to joint angle manipulations, that display

more tonic patterns of synaptic activity [14��](Figure 2b). Thus, inputs with a low background firing

rate might preferentially encode stimulus onset.

As with cells that respond to joint rotation, many granule

cells in the flocculus exhibit comparatively high rates of

tonic activity. In this region, vestibular stimulation pro-

duces a modulation of the EPSC frequency that linearly

correlates with the velocity of motion (rather than with

position or acceleration) [17��]. A high rate of spontaneous

activity allows the representation of motion velocity to be

signalled not only by an increase, but also by a decrease in

EPSC frequency, to indicate motion in the preferred and

non-preferred direction, respectively. Synaptic activity in

granule cells with low baseline rates is often completely

silenced during movements at high velocities in the non-

preferred direction, and further increasing velocities can

no longer be represented. Therefore, in the flocculus a

high spontaneous EPSC rate shifts the dynamic range of

MF inputs to enable granule cells to detect motion in

both directions.

The pattern of evoked synaptic activity in granule cells

can also differ between distinct sensory afferent pathways

signalling the same stimulus. For example, cutaneous

electrical stimulation of the forepaw is signalled by both

the cuneate and lateral reticular nucleus [15�]. Those two

pathways give rise to distinct populations of MFs, form

synapses onto non-overlapping populations of granule

cells and signal the stimulus with differential onset

latencies and overall patterning.

Therefore it appears that in different regions of the cerebel-

lum, the MF–granule cell synapse signals different features

of sensory stimuli. Whisker-evoked onset responses in crus

I and IIa are potentially used to report whisker collision

with an object, whilst synapses in the anterior paravermis

indicate the onset, duration and intensity of touch or joint

movement. For vestibular signalling, synaptic activity

reflects both the direction and velocity of motion.

Accuracy of sensory transmission throughMF–granule cell synapsesSince granule cells receive very few MF inputs [1,2],

distinct connections can be discerned electrophysiologi-

Current Opinion in Neurobiology 2009, 19:445–451

448 Sensory systems

Figure 3

Motion encoding by MF–granule cell synapses. (a) Peristimulus time

histogram showing EPSC frequencies per 100 ms time bin for a granule

cell in the flocculus in which two populations of synaptic responses

could be distinguished on the basis of their amplitude distribution.

Vestibular stimulation by horizontal rotation of the mouse (the velocity of

the motion is indicated by the top trace) modulates the activity of one

input (input 1, blue), but not another (input 2, black), to the same granule

cell. (b1) Using Bayes’ rule, the stimulus most likely to have evoked a

given response can be reconstructed. Plotted are example stimulus

estimates of the velocity of motion (top left) for a single trial for 1, 12 and

100 MF inputs. (b2) (Scaled) Gaussian fits to the distributions of the

mean error of the stimulus estimate based on the indicated number of

inputs [17��]. The reliability (standard deviation of the error) and accuracy

(mean error) improves with the number of MF–granule cell synapses.

cally based on the amplitude distributions of postsynaptic

responses [14��,17��]. Also, sensory-evoked responses

(Figure 2) can often be signalled by a single MF input

[13�,17��], as indicated by the comparison of evoked

presynaptic spiking activity with postsynaptic currents

[11,13�,14��,15�,17��]. This is consistent with obser-

vations that the coefficient of variation of EPSC ampli-

tudes during sensory signalling is very similar to that

recorded for single MF input stimulation in slices

[17��,30]. Thus, in many cases, individual MF inputs

onto a granule cell can be discerned and monitored

(Figure 3a [14��,17��]) making it possible to study sensory

signalling at the most fundamental level.

Knowing the accuracy of synaptic signalling will tell us to

what extent individual granule cells contribute to sensory

representation. This question has been explored in the

flocculus (Figure 3a), where a highly quantitative and

time-varying vestibular stimulus (with motion velocities

of up to 608/s) has been used to quantify synaptic signal-

ling over a large region of stimulus space [17��]. In these

cells, EPSC frequency correlates with motion velocity,

and since EPSC amplitude and charge remain constant

over the stimulus, this, further ensures linear synaptic

representation over a large region of stimulus space

[17��,33�,38].

In individual floccular granule cells, averaging the ves-

tibular-evoked responses over many trials shows that the

EPSC frequency reflects a reliable and broadly tuned

velocity-encoding synapse. Although this analytical

approach is useful for obtaining an indication of what

the recorded activity represents, it fails to report anything

about the reliability of such representations during an

individual stimulation epoch. These whole-cell data have

therefore been used for Bayesian reconstructions of the

vestibular stimulus to estimate the reliability of velocity

representation signalled by individual synapses and popu-

lations of granule cells. On the basis of the recorded

EPSC frequency, these analyses show that during a single

trial, one synapse reliably signals the direction of motion

[17��]. Whilst the estimates of the velocity of motion based

on one synapse show substantial errors, velocity is accu-

rately reported by averaging over only�100 MF - granule

cell synapses (Figure 3b). Thus, even if all four inputs to

an individual granule cell were dedicated to providing

velocity information, the combined signal would still be

significantly poorer than the signal relayed by the primary

vestibular afferents [39�]. Why then have so many granule

cells receiving very few inputs, given that, even collec-

tively, four inputs are rather poor at reliably transmitting

velocity signals?

What do granule cells compute?The type of information granule cells translate to Purkinje

cells will be determined by the functional homogeneity

of MFs they receive information from, combined with

Current Opinion in Neurobiology 2009, 19:445–451

the efficacy of those inputs in driving the granule cell to

spike. The reliability of this translation will depend not

only on the fidelity of synaptic and spiking activity in

granule cells, but also on the very nature of the stimulus

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Sensory representations in cerebellar granule cells Arenz, Bracey and Margrie 449

Figure 4

Models of granule cell function. (a) The pattern generation/separation

principle. (a1) Different subsets of MFs onto a given granule cell carry

information about different modalities or receptive fields (blue, red,

yellow and green). Assuming that more than one MF input is required to

evoke granule cell spiking, synaptic coincidence arising from functionally

distinct inputs (grey shading, left) will result in new patterns of AP activity

(grey shading, right). In the case of the flocculus, horizontal direction

information arising from vestibular canal activation (blue) is provided by a

single MF input [17��], to be integrated with other motion-related

information. (a2) Whilst individual multimodal GCs reliably indicate the

direction of motion (potentially in combination with other movement-

related signals), accurate velocity information is inherent in the

population of GCs (blue shading) to be read out by Purkinje cells. (b) The

similar coding principle. All MFs onto a given granule cell carry

information about the same modality (and even submodality) and

receptive field (purple), as observed for granule cells in the anterior

paravermis in the cat. Under these conditions, the granule cell is

hypothesised to relay the MF activity (grey shading left, right), whilst

filtering out non-synchronous signals occurring in individual MFs

regarded as noise [14��].

(or stimuli) being represented. For example, a burst of

synaptic activity at a single synapse can presumably

indicate a basic feature of a stimulus, such as the onset,

more reliably than encoding more complex stimulus fea-

tures such as intensity. Thus, whilst the velocity of motion

is a complex feature that requires high resolution signalling

achieved only by populations of granule cells, individual

cells can reliably detect stimulus features such as motion

direction using only one of their four synaptic inputs.

If one MF input were sufficient to drive spiking, a granule

cell would act in the simplest case as a relay. If two or

more inputs are required, information processing strongly

depends on the functional convergence of the inputs, and

granule cells might perform more complex computations.

Several studies suggest that two or more EPSPs are

required to drive a granule cell above spike threshold

[12��,14��,28,40], but whether these EPSPs in vivo typi-

cally arise from the same or different MF inputs is yet to

be resolved. In vitro, high frequency stimulation of single

MFs at 100–600 Hz [13�,37] or of two MFs at 50 Hz [28]

can evoke granule cell spiking. However, several of these

studies were carried out under high calcium conditions

[28,37] where synaptic responses are substantially larger

[30] than those recorded in vivo (7–45 pA) [12��,13�,17��]or in vitro under more physiological concentrations of

calcium (10–45 pA) [13�,30,32]. Nevertheless it is reason-

able to assume that single MF discharge at high frequen-

cies in vivo could evoke granule cell firing [13�], reflecting

the simplest form of granule cell computation that may

signal a basic feature such as stimulus onset.

However other in vivo studies in the anterior paravermis

indicate that synchronous input from multiple MFs is

required to depolarise the granule cell to spike [14��].In the flocculus, vestibular-sensitive MF activity is tonic,

occurring predominantly over the range of 0–100 Hz over

a large region of stimulus space. This is less than the

anticipated firing frequency needed by one MF to drive a

granule cell beyond threshold, which therefore indicates

that direction-encoding granule cells would require

coincidence of a second synaptic input. The implications

of the requirement for two coincidentally active inputs

must then depend on the functional wiring.

On the one hand all MFs innervating a given granule cell

could be functionally different, enabling granule cells to

integrate information and generate new patterns of activity

[3,4] (Figure 4a1). This scheme of integration is supported

by the fact that whisker-evoked synaptic responses in

granule cells in crus I and IIa are carried by single MF

inputs [13�]. Similarly, in floccular granule cells velocity

information is signalled by a single MF input during

horizontal rotation [17��] (Figure 3a). In this scheme the

remaining MF inputs would be available for encoding

information from other vestibular organs (i.e. other axes

of rotation or linear acceleration) or different modalities.

www.sciencedirect.com Current Opinion in Neurobiology 2009, 19:445–451

450 Sensory systems

Since the low EPSC frequencies during vestibular stimu-

lation indicate the requirement for additional MF inputs to

reach spike threshold, granule cells potentially signal

coincidence of different movement-related stimuli (e.g.

visual motion or eye movement-related signals that are

signalled to the flocculus [18,19]). Thus, whilst individual

granule cells can reliably signal the direction together with

other motion-related features, in this scheme the postsyn-

aptic PC extracts reliable velocity information contained in

the activity of a small population of granule cell inputs

(Figure 4a2).

On the other hand, in the anterior paravermis an alterna-

tive functional wiring pattern exists where distinct inputs

to a given granule cell have functionally similar receptive

fields and encode the stimulus using very similar synaptic

patterns (similar coding principle, Figure 4b) [14��,15�].In these cells highly synchronous activity in multiple MF

inputs is required to produce sufficient depolarisation for

GC spiking [14��,41]. Here, granule cells therefore serve

as a relay whereby only synchronous input is conveyed

whilst non-synchronous MF signals are regarded as noise

and filtered out.

Concluding remarksIn vivo whole-cell recordings from granule cells indicate

that sensory-evoked patterns of synaptic activity are

region and modality specific, varying from bursting to

tonic responses. In the anterior paravermis the two or

more inputs required to discharge a granule cell provide

very similar information to improve stimulus-evoked

signal to noise ratios [14��,15�,41]. In contrast to this

unimodal operation, granule cells in the flocculus inte-

grate information from functionally different MFs [17��],which is proposed to result in the generation of new

activity patterns. Whilst individual MF–granule cell

synapses reliably indicate motion direction on a single

trial basis, the velocity of motion is accurately encoded by

averaging over small populations of granule cells. In this

way, the new patterns of granule cell activity resulting

from integration of two or more inputs would deliver

motion-related information to the cerebellar output

neurons in a sparse fashion [3,4,42].

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