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 ([email protected])
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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