Presynaptic plasticity at cerebellar parallel fiber terminals
Marie-Capucine Le Guen, MNeuroScia Chris I. De Zeeuw, MD, PhDa,b a Department of Neuroscience, Erasmus MC Rotterdam, The Netherlands b Netherlands Institute for Neuroscience Royal Academy of Arts and Sciences (KNAW) Amsterdam, The Netherlands
Correspondence to: Chris I. De Zeeuw Dr. Molewaterplein 50 3015 GE, Rotterdam, The Netherlands E-mail:
[email protected] Abstract The cerebellum plays a role in the control of sensorimotor functions and possibly also of higher cognitive processing. The granule cells, which are abundant and unique in their characteristic dendritic morphology, allow the cerebellum to combine the advantages of sparse coding with a high sensitivity for individual afferents at the input stage. Plastic changes in the granular layer circuitry may thus control instant transformation of inputs as well as long-term modifications so as to support procedural memory formation. Over recent decades, substantial research has been done to explore the mechanisms of postsynaptic changes that may sustain learning processes in the cerebellum, especially bidirectional plasticity at the parallel fiber to Purkinje cell synapse. In contrast, the presynaptic occurrence of synaptic plasticity has been relatively neglected. Here we review the current models of granular layer processing in the framework of cerebellar functioning with special emphasis on the presynaptic modulations of operations at the parallel fiber to Purkinje cell synapse. We argue that the wide range of possible mechanisms that can strengthen the parallel fiber to Purkinje cell synapse at the presynaptic level endows the cerebellar cortex with optimal computational capacities to potentiate both spatial and temporal cues that are relevant for fine-regulating memory formation. KEY WORDS: cerebellum, computation, granular layer, motor learning, potentiation
Introduction The cerebellum has long been identified as an essential structure for sensorimotor control (1), and alteration in its function can result in a dramatic neurological motor syndrome called cerebellar ataxia (2,3) as well as behavioral changes in some major psychological disorders Functional Neurology 2010; 25(3): 141-151
such as autism and schizophrenia (3). Over recent decades, the cerebellum has been demonstrated to contribute to many types of motor function, ranging from control of basic reflexes [e.g. vestibular reflexes; (4)] to control of voluntary movements, both single-joint [e.g. eye movements (5)] and multi-joint [e.g. arm movements (6)]. In addition, recent studies advocate the possibility that the cerebellum can be involved in higher cognitive functions, for instance language processing (7), attention and executive control (8). The cerebellum has gained much of its popularity from the intriguing matrix-like organization of its cortex. Indeed the wide variety of cerebellar functions are probably all controlled by specific modules, which are built upon the same cytoarchitetural principles, but connected with different input and output nuclei (1,9). This uniformity across the cerebellar cortex and olivocerebellar system implies a similar way of processing, yet the physiological mechanisms of cerebellar information processing remain partly obscure. The great number of parallel fiber (Pf) connections between granule cells and Purkinje cells (PCs), which deliver the final cerebellar cortical output, makes the parallel fiber to Purkinje cell (Pf-PC) synapse an interesting place to study putative mechanisms that may underlie cerebellar learning. Indeed, functional models of the olivocerebellar system present the granular layer as the baseline input structure that is required for control of both spatial and temporal aspects of motor coordination (10). From this perspective, plasticity of granule cell synapses is essential for the establishment and fine-tuning of networks recruiting specific groups of granule cells, optimizing the advantages of sparse coding combined with a high sensitivity for individual mossy fiber afferents. Several papers have already reviewed the different forms of plasticity identified in the cerebellum (11-13), in particular long-term depression (LTD); recently, however, also long-term potentiation (LTP) at the Pf-PC synapse has been shown to be functional (14). Most of these papers focus particularly on the postsynaptic changes responsible for synaptic strength modulation. Presynaptic events, on the other hand, have been relatively neglected, even though they can have a strong impact on neurotransmission (15-17). Here we review current models of olivocerebellar computation from the perspective of granular layer processing with special emphasis on presynaptic plasticity at the synapses that granule cells form via their Pfs with the PCs, and the presynaptic molecular mechanisms underlying this type of plasticity. We conclude that the rich repertoire of possible presynaptic modifications of synaptic strength between granule cells and PCs endows the system with enormous computational power to selectively strengthen specific spatiotemporal components of sensorimotor events at a high resolution.
141
M.-C. Le Guen & C.I. De Zeeuw
Position and function of granule cells in the cerebellar circuitry
Connectivity of granule cells The cerebellar circuitry is essentially composed of a relay station in the cerebellar nuclei (CN) and a cortical ‘side-loop’. The ultimate cerebellar output originates in the CN, which receive their main excitatory input directly via mossy fiber and climbing fiber collaterals that relay information from predominantly spino-pontine nuclei and the inferior olive, respectively. The cerebellar cortex channels these two main excitatory inputs into one main inhibitory output provided by the PCs. The granule cells play a critical role in this transformation: via their Pfs they transfer all the mossy fiber inputs directly to the dendrites of the PCs. They provide each PC with about 150,000 to 200,000 synaptic Pf contacts onto its dendrites. Since each Pf makes only a few synapses on a single PC, probably more than about 50 Pfs have to be activated simultaneously to evoke, postsynaptically in the PC, an additional supra-threshold response, the socalled simple spike (18). In contrast, a climbing fiber forms a powerful contact involving hundreds of synapses onto an individual PC and its activity always evokes a large response in the PC, the ‘complex spike’ (19). In addition, the Pfs innervate interneurons; these include the stellate cells and basket cells in the molecular layer as well as the Golgi cells (GCs) in the granular layer. Via the molecular layer interneurons the Pfs provide a feedforward inhibition to PCs, whereas via the GCs they provide a feedback inhibitory loop to the granule cells. This organization is uniform across the entire cerebellar cortex, which implies that information is processed analogously despite the different inputs and outputs of the various cerebellar modules (1,9). Since the granule cells are in a critical position in the cerebellar network, they must contribute to the overall function of the cerebellum (20). The Marr-Albus hypothesis developed during the early 1970s introduced a concept of how the cerebellum and granular layer may be involved in motor learning (21,22). This model suggests that alterations in the strength of Pf synapses underlie the formation and storage of procedural memories. It was originally supported by the discovery of a form of LTD at the Pf-PC synapse (13). Indeed, when PCs receive simultaneous inputs from Pf and climbing fibers, the transmission at the Pf-PC synapse is weakened, thereby potentially diminishing PC inhibition on CNs. However, more recently evidence has been emerging that most granule cells, at least in the anesthetized preparation, are silent to begin with (23,24) and that actually LTP of these silent Pf-PC synapses is required for cerebellar motor learning (14). In either case, regardless of the dominant type of postsynaptic mechanism, LTD or LTP, a granular layer is needed, in which the information is optimally recoded, redistributed, and modified.
Granule cells and sparse recoding of information The Marr-Albus model of cerebellar learning (21,22) assumes that processing in the granular layer is based on a spatial-pattern separation and redistribution of mossy fiber information among specific and larger groups of granule cells. This re-organization would ultimately gen-
142
erate a sparse and expanded representation of inputs. In addition, rate coding of incoming signals should allow the control of input gain of the mossy fiber to granule cell transmission (21,22). Because the cerebellum is able to process information at an outstanding velocity, the rate coding underlying the gain control theory has been questioned. Recently, first-spike delay determination has been suggested to be a more reliable coding strategy, considering the limited period of time in which the cerebellum has to operate (10).
Timing and plasticity in the granular layer In addition to its control of motor information input gain, the granular layer is also supposed to contribute to the timing of cerebellar computation (10). Golgi cells are of particular importance in this theory, as their feedforward inhibition of granule cells has been suggested to be responsible for the generation of a time-window, corresponding to a limited period of time during which granule cells can produce spikes in response to mossy fiber stimulation. Temporal dynamics in the cerebellar cortex could be generated by the synchronization of this timewindow over specific areas of the granular layer (25). From this perspective, plasticity at the Pf-GC synapse could affect the duration of the time-window, and the resulting temporal coding of inputs (26). A second essential process in granular layer control of cerebellar timing is presynaptic plasticity at the mossy fiber to granule cell synapse. Indeed, LTP and LTD at this synapse are supposed to control the first-spike delay of the granule cell response to burst mossy fiber stimulation, driving spikes inside or beyond the time-window. This ‘windowmatching’ effect would fine-tune the timing of granule cell firing (10). Finally, the third point of control of timing in the granular layer lies in the plasticity at the Pf-PC synapses. Indeed spike timing in granule cells combined with the modulation of release probability at Pf synapses may shape the synchrony of their activation, an important requirement for the generation of simple spikes in PCs (24).
Granular layer oscillations An important property of the cerebellar circuitry resides in its oscillatory activities, and the granular layer is thought to contribute at least partly to this internal rhythm of the cerebellum (27,28). Indeed, synchronized low-frequency oscillations, which have been reported for large areas of the granular layer (29,30), can be associated with sensorimotor control (31). A correlation has been found between these granular rhythms and low-frequency oscillations in the sensorimotor cortex (32,33), which could mediate the communication between the cerebellum and cortico-thalamic structures (27,28). In addition, computational predictions indicate the capability of the granular layer to generate high-frequency oscillations (34). These models strongly imply an involvement of the double, feedforward and feedbackward, GC inhibitory loops, as suggested in the ‘time-window matching’ hypothesis (10), and may be crucial for the realization and stabilization of well-timed movements. Functional Neurology 2010; 25(3): 141-151
Presynaptic parallel fiber plasticity
Presynaptic plasticity of parallel fibers
At Purkinje cells If the postsynaptic mechanisms at the Pf-PC synapse are indeed dominated by LTP rather than LTD (14,35), one might expect the presynaptic, physiological and molecular operations to act in line with a postsynaptic strengthening rather than a weakening of the Pf-PC synapse. In other words, it would not make sense if depression prevailed at the presynaptic level, while the postsynaptic machinery was dedicated to potentiation. Presynaptic LTP of the Pf-PC synapse (prePf-LTP) can indeed readily occur following repetitive stimulation of the Pfs at low frequencies (2-8 Hz), when climbing fiber activity is absent (36-42). Importantly, this frequency corresponds well to the frequency of Pf stimulation that induces postsynaptic LTP (14,43). PrePf-LTP is induced by a rise in Ca2+ in the presynaptic terminal, which activates Ca2+-sensitive adenylyl cyclase 1 (AC1). AC1 in turn induces a rise in presynaptic cyclic adenosine triphosphate (cAMP) concentration and subsequent activation of the protein kinase A (PKA) (6) pathway (39,44). The increase in neurotransmitter release observed after induction of prePf-LTP seems to result from modification of the active zone proteins RIM1α and Rab3 by the activated PKA (45-47) and co-activation of the nitric oxide (NO) pathway (48,49). In addition to long-term changes in presynaptic transmission, four forms of presynaptic short-term plasticity have been described for Pf-PC synapses: a strong paired-pulse facilitation (PPF), endocannabinoid-mediated depression, a post-tetanic potentiation (PTP) and a form of short-term potentiation of longer duration (STP). Because Pf-PC synapses can show a marked facilitation of synaptic transmission following paired-pulse Pf stimulation, PPF at these synapses has been studied extensively in the context of the residual Ca2+ hypothesis (50,51) (see also next page). High-frequency brief burst stimulation of Pfs (10 stimuli at 50 Hz) can induce both enhancement and depression of Pf-PC synapses. Indeed, in these conditions, Pf-PC synapses can express synaptically-induced suppression of excitation [SSE; (52,53)] mediated by a retrograde action of endocannabinoids (eCBs) in Pf terminals, following activation of presynaptic CB1 receptors (54). In line with the induction of postsynaptic LTD, co-activation of climbing fiber and Pf-PC synapses can enhance eCB retrograde inhibition of Pf transmission (55). In the presence of CB1 receptor antagonists, however, similar stimulus trains evoke PTP (52). STP of synaptic efficacy between Pf and PCs can be evoked by periodic burst stimulation of Pfs [periodic bursts of 5 stimuli at 50 Hz, for 90s at a frequency of 1Hz; (56)], and it lasts for 20 to 30 minutes. The underlying signaling pathway is not quite clear, but it has been suggested that STP may represent an early phase of prePf-LTP, thereby acting through the same pathway involving cAMP, PKA and RIM1α (56).
At interneurons In addition to their connections with PCs, Pfs also contact the dendrites of the stellate cells (SCs), basket cells (BCs) and GCs. Pf synaptic contacts onto SCs (Pf-SC synapses) and BCs (Pf-BC synapses) exhibit different Functional Neurology 2010; 25(3): 141-151
types of short-term plasticity in response to high-frequency granule cell stimulation (50 Hz). Whereas Pf-BC synapses may show facilitation, Pf-BC synapses show depression. Pf-BC synaptic depression depends on Munc13 activation, which may affect vesicle release probability (57). These short-term changes at Pf to molecular layer interneuron (MLI) synapses could be important in the selective modulation of the feedforward inhibition exerted on the different compartments (i.e. dendrites or soma) of the PCs (57). Short-term inhibition of Pf-MLI synaptic strength by eCB retrograde signaling has also been demonstrated in the presence of strong Pf activity [10 stimuli at 50 Hz; (58)]. To date, relatively little plasticity has been identified presynaptically at PfGC synapses. Comparison of short-term plasticity mechanisms at Pf-PC and Pf-GC synapses (52) has shown that train stimulation of Pfs (10 stimuli at 50 Hz) can induce PPF of Pf-GC synapses, but no eCB-dependent PTP.
Molecular mechanisms of presynaptic parallel fiber plasticity Several conditions must be met before a change in synaptic strength can qualify as plasticity. In our above description of presynaptic plasticity at granule cell synapses, we adhered to the following definition, developed by leading researchers in the science of memory: “plasticity is a use-dependent, structural change at the cellular level in the nervous system, which is necessary and sufficient to induce long-lasting functional changes that are usually beneficial for the organism” (59). However, many molecular mechanisms have been reported to induce presynaptic changes at the Pf terminal, while one or more of the components in this definition have not yet been met. Here we review all the molecular pathways that have been suggested to be involved in presynaptic Pf plasticity or to modulate related pathways (Fig. 1, see over).
Adenylyl cyclase - protein kinase A signaling pathway The main conjecture regarding the molecular mechanisms underlying prePf-LTP is that an initial presynaptic rise in Ca+ activates a Ca2+-sensitive adenylyl cyclase, which increases intracellular cAMP levels and leads to PKA activation (39,60). In line with this view, the Ca2+/calmodulin-sensitive AC1 is highly expressed in cerebellar granule cells (61), and AC1 knockout mice show deficits in cerebellar motor performance that may partly be due to learning deficits (42). In cultured cerebellar neurons, application of adenylyl cyclase activator forskolin or membrane-permeable cAMP analogs causes long-lasting potentiation of Pf-PC synaptic transmission, while inhibiting PKA activity blocks induction of potentiation (39,41,62). Together with Hirano’s finding (37) that repetitive stimulation of granule cells results in an increased probability of neurotransmitter release, while the quantum size remains unchanged, these results suggest that PKA acts at the presynaptic site by phosphorylating vesicle-release related proteins. PKA substrates include some major presynaptic proteins such as rabphilin (63), synapsin I and synapsin II (64), and
143
M.-C. Le Guen & C.I. De Zeeuw
Figure 1 - Molecular mechanisms potentially modulating neurotransmitter release presynaptically at the parallel fiber to Purkinje cell synapse. Many molecular mechanisms can affect glutamate release at the parallel fiber to Pukinje cell synapse, including the AC1/PKA/cAMP pathway, which mediates presynaptic parallel fiber LTP (in red transparent area), activation of presynaptic receptors, which can inhibit (in blue) or potentiate (in green) voltage-gated Ca2+ channels, and proteosomal degradation of synaptic proteins (in yellow). However, there are still many gaps in the description of these pathways, and we highlighted with red arrows the interactions that need to be confirmed at parallel fiber synapses by further investigation. Black arrows indicate positive (→) or negative (––•) interactions. Dotted arrows indicate protein or molecule trafficking. A1=adenosine receptor 1; AMPA=α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; ATP=adenosine triphosphate; CaMKII=calmodulin kinase II; cAMP=cyclic adenosine mono-phosphate; CB1R=cannabinoid 1 receptor; E1=Ubiquitin-activating enzyme; E2=Ubiquitin-conjugating enzyme; Gi/o=G-protein; GABAa/b=γ-aminobutyric acid receptor type a/b; KAR=kainate receptor; mGluR1/4=metabotropic glutamate receptor 1/4; MLIs=molecular layer interneurons; P=phosphoryl group; P2Y/X=purinergic receptors type X/Y; PKA=protein kinase A; Rab3A=Rab-protein 3; 14-3-3=adaptor 14-3-3; RIM1α=regulating synaptic membrane exocytosis 1alpha; SNAREs=core {soluble-NSF-attachment protein receptors} complex; Trim3=Tripartite motif protein 3; Ub=Ubiquitin; VGCC=voltage-gated Ca2+ channel; VGNa=voltage-gated sodium channel.
possibly also RIM1α (46). Indeed prePf-LTP is abolished in mice lacking the active zone protein RIM1α (46) and these mice do show learning deficits (65). Lonart et al. (47) suggested that phosphorylation of RIM1α at a single site, serine 413, is required for LTP of neurotransmitter release at Pf synapses and allows RIM1α to interact with the adapter protein 14-3-3 (66). However, mice in which Ser413 is replaced by alanine, preventing phosphorylation, do not exhibit alterations in presynaptic PfPC LTP or learning deficits (67). Therefore, further investigations are necessary to identify the PKA targets at presynaptic terminals that could affect neurotransmitter release. The vesicular protein Rab3A, which interacts with RIM1α phosphorylation, has been shown to be essential for presynaptic LTP in hippocampal mossy fibers (45), and might be involved in PrePf-LTP as well.
Role of residual calcium Although the molecular mechanisms mediating the various forms of short-term plasticity are not fully understood yet, they are all known to be Ca2+-dependent (50). Neurotransmitter release occurs via exocytosis of synaptic vesicles, which is triggered by a rise in intraterminal Ca2+ concentration. This rapid increase disrupts the resting condition of the presynaptic terminal, and compensatory mechanisms are activated to re-establish the equilibrium. However, during repetitive stimulation of nerve terminals, these processes may not be sufficient
144
to pump out all the Ca2+, allowing residual amounts to accumulate. This accumulation of residual Ca2+ in Pf terminals has been shown to enhance neurotransmitter release (68). Residual Ca2+ has been suggested to be essential in the facilitation of neurotransmitter release during short-term presynaptic plasticity (50), and is probably responsible for the strong PPF at the Pf-PC synapse.
Regulation of transmitter release by presynaptic receptors Synaptic transmission is based on the release, by the presynaptic neuron, of neurotransmitters that activate specific receptors on the postsynaptic site. Yet some of these receptors are also expressed at the terminal of the presynaptic neuron. These presynaptic receptors can be activated either by the same neurotransmitters that are released by the neuron itself (autoreceptors) or by other neurotransmitters released by neurons in the vicinity (heteroreceptors). At many inhibitory and excitatory synapses in the CNS, presynaptic receptors are involved in the regulation of synaptic transmission, thereby modulating important brain functions such as working memory (69,70) and pain sensation (71). Pf terminals also contain many types of presynaptic receptors (Table 1), which can be activated under certain stimulus conditions. They can modify synaptic transmission via signaling pathways that have been only partly identified, but Functional Neurology 2010; 25(3): 141-151
Presynaptic parallel fiber plasticity
Table I - Presynaptic receptors at granule cell synapses Neuromodulator
Receptor
Synapse
Synaptic change
Parallel fiber stimulation
mGluR4
Pf-PC
–
?
glutamate
purines (ATP) purines (adenosine)
Ref 90, 91
presynaptic
Pf-PC Pf-MLIs
+
low-frequency
kainates
–
high-frequency
GABAa
Pf-PC Pf-MLIs
+
GABAb
Pf-PC
–
CB1
Pf-PC Pf-MLIs
–
high-frequency bursts
postsynaptic
53, 78
Pf-PC
+
?
multiple
111, 112
Pf-PC
–
high-frequency
presynaptic
103
GABA
eCBs
Source of neuromodulator
P2Y P2X A1
X
118
molecular layer interneurons
106 94, 95
Many presynaptic receptors are expressed and functional at parallel fiber to Purkinje cell synapses (Pf-PC) and parallel fiber to molecular layer interneuron synapses (Pf-MLI). Neuromodulator release, and thereby receptor activation, depends on parallel fiber activity, molecular layer interneuron activity or Purkinje cell activity. Abbreviations and symbols: X=not relevant; ?=not reported in literature; +=potentiation; - =depression; ATP=adenosine triphosphate; CB1=cannabinoid receptor 1; mGluR4=metabotropic glutamate receptor 4; eCBs=endocannabinoids; GABA=γ-aminobutyric acid; GABAa/b=γ-aminobutyric acid receptor type a/b.
which generally include direct or indirect activation of voltage-gated Ca2+ channels (VGCCs), or modification of the release machinery itself.
Direct inhibition of voltage-gated Ca2+ channels eCB-mediated regulation of neurotransmitter release is a widespread mechanism for regulating synaptic strength in a retrograde fashion (72). Autoradiographic and immunohistochemical studies have reported expression of the CB1 receptor in Pfs (73,74), and many studies have shown that agonist-mediated presynaptic CB1 receptor activation acutely depresses excitatory synaptic transmission of Pf-PC synapses by lowering the probability of transmitter release (75). Presynaptic depression of inhibitory synapses induced by a brief depolarization of the postsynaptic cell and mediated by the action of retrograde messengers had already been reported for a decade in the cerebellum and hippocampus before it was demonstrated at the excitatory Pf-PC synapse. This process, called depolarization-evoked suppression of excitatory synapses (DSE), is blocked by CB1 receptor antagonists (76,77) and does not occur in CB1 receptor knockout mice (78). While the conditions that might give rise to DSE in vivo are not known, Brown et al. (53) clarified the mechanism of eCB-mediated inhibition of synaptic transmission by stimulating Pfs under conditions similar to those encountered in vivo, producing brief bursts of synaptic activity (10 stimuli at 50 Hz). They reported activation of postsynaptic AMPA and mGluR1 receptors, which trigger the release, by the PCs, of eCBs in the synaptic cleft. Accordingly, pharmacological studies reported eCB release and retrograde synaptic inhibition of Pf-PC synapses following bath administration of mGluR1 agonists (77,79). On the presynaptic side, Brown et al. (53) described retrograde inhibition of Pf transmission, later described as synapticallyevoked SSE. Surprisingly, SSE spreads relatively little Functional Neurology 2010; 25(3): 141-151
to neighboring cells, the inhibition remaining localized to the activated Pfs. Therefore, it is likely that eCB-mediated inhibition of neurotransmission depends on localized release of glutamate and mGluR1 activation, as well as on the re-uptake and degradation mechanisms that prevent messengers from spreading over significant distances (54). The role of CB1 receptors in SSE has also been confirmed by blockage studies using CB1 receptor knockout mice (78) or CB1 receptor antagonists (79). Activation of CB1 receptors on Pf terminals inhibits presynaptic Ca2+ channels, resulting in a reduction of presynaptic Ca2+ entry and thereby lowering the probability of transmitter release while increasing the pairedpulse ratio (53,76). CB1R-mediated inhibition of VGCCs occurs via a direct action of CB1R-coupled GI protein on Ca2+ channels (80). Similar mechanisms of eCB-mediated DSE and SSE have been demonstrated at the Pf-MLI synapse (58). In this case, however, the release of eCBs by SCs depends on the activation of postsynaptic mGluR1 and NMDA receptors. Interrupting eCB retrograde signalling by deleting CB1 receptors in globally mutant mice affecting both Pf-PC and Pf-MLI synapses can diminish discrete motor learning (81). A large body of evidence has been collected showing the expression of mGluR4 in cerebellar granule cells. Reverse transcription-PCR analysis has shown that group III mGluR mRNA is expressed in cultured granule cells (82), and several in situ hybridization studies have demonstrated high levels of mGluR4 mRNA in granule cells (83,84). In addition, immunohistochemical studies have shown that mGluR4 expression is localized presynaptically at the Pf-PC synapse (85,86) and that these metabotropic receptors form clusters at the membrane of Pf terminals (86). Knockout mice of mGluR4 indeed support a role for this receptor in the inhibitory control of glutamatergic synaptic transmission at the Pf-PC synapse, and they do show motor deficits on the rotarod test (87). Moreover, application of the selective group
145
M.-C. Le Guen & C.I. De Zeeuw
III mGluR agonist L-AP4 results in a depression of Pf-PC synaptic transmission indicating an autoreceptive function of these mGluRs (88,89). Even though mGluR localization studies strongly indicated that mGluR4 was the one implicated in Pf-PC glutamatergic depression, the use of group III mGluR-specific agonists did not allow definite identification of their respective action. Recently, it was shown with the use of a specific mGluR4 modulator that the inhibitory control of group III mGluRs on Pf-PC transmission is exclusively mediated by the activation of mGluR4 autoreceptors (90). As group III mGluR agonist administration causes a transient decrease in presynaptic Ca2+ influx evoked by Pf stimulation (91), mGluR4-mediated modulation of synaptic transmission was supposed to involve inhibition of VGCCs. However, the physiological relevance of mGluR4 function as an autoreceptor can be questioned, because endogenous release of glutamate via pairedpulse or high-frequency stimulation of Pfs is ineffective in modifying synaptic strength (89). One explanation may be that additional regulatory mechanisms upstream, not yet identified, are involved in the activity-dependent activation of presynaptic mGluR4 (89). Another possibility, which we will develop below, is that part of the mGluR4 transduction pathway acts on some steps downstream. In the cerebellum, GABAb receptors show high levels of expression in the molecular layer and moderate levels of expression in the granular layer, as shown by pharmacological studies (92,93), in vitro receptor autoradiography (94,95) and in situ hybridization (96). Furthermore, in situ hybridization on human and rat cerebellar cortex slices revealed a differential distribution of the GRIB1a and GRIB1b splice variants of GABAb mRNA, suggesting a presynaptic localization of the GRIB1a isoform at Pfs (96). These GABAb receptors are probably functional, as both the presynaptic Ca+ influx in Pf terminals and Pf-PC synaptic transmission are reduced following administration of GABAb agonist baclofen (97). Further investigations have revealed the heterosynaptic character of GABAb-mediated depression at the Pf-PC synapse, since it is induced by the brief and widespread elevation in extracellular GABA concentrations following stimulation of MLIs (98). Baclofen synaptic inhibition is primarily mediated by Gi/o modification of GABAb-coupled VGCCs (97), with possible additional presynaptic effects downstream of Ca2+ entry. Expression of adenosine A1 receptors (A1Rs) in rat and mice cerebellar cortices has been reported in both immunohistological and autoradiographical studies; they predominantly occur in the molecular layer (99,100). The substantial reduction of A1Rs in weaver mice (99), which lack granule cells, points towards a sub-cellular localization of A1Rs at the Pfs. This view is supported by pharmacological studies, which show modulation of Pf synaptic activity by adenosine (97,101,102). Whole-cell recordings of PCs have shown that activation of presynaptic A1Rs reduces glutamate release (102). A1R inhibition of the evoked excitatory input to PCs is mediated by an attenuation of the presynaptic Ca2+ influx in Pf terminals via GI/O downregulation of VGCC activity (97,103). In principle, many different processes could explain the origin of extracellular adenosine in the cerebellum (104), including both a direct release by the terminals or a degradation of ex-
146
tracellular ATP to adenosine. At the Pf-PC synapse, however, the activity-dependent production of adenosine (103,105) suggests a substantial release of adenosine by the Pfs themselves, the A1Rs thereby acting as autoreceptors.
Indirect activation of VGCCs A combined immunocytochemical and electrophysiological study by Stell et al. (106) reports the expression of functional GABAa receptors on the membrane of Pf terminals. Agonist-mediated activation of presynaptic GABAa receptors has been shown to potentiate synaptic transmission to both PCs and MLIs by increasing glutamate release via a mechanism dependent on voltagegated sodium channel activity. Interestingly, the synaptically-evoked release of GABA by MLIs mediates a similar increase in Pf synaptic transmission. Thus, these observations suggest a signaling pathway in which activation of presynaptic GABAa receptors following MLI activity depolarizes the membrane of the Pfs beyond the threshold of voltage-dependent Na+ channels. The opening of these Na+ channels would then lead to activation of VGCCs and thereby induce the release of glutamate.
Modification of the vesicle release machinery In addition to their direct action on the Ca2+ transient through the VGCCs, CB1 receptors can inhibit AC1 activity, thereby modulating prePf-LTP. Indeed, activation of presynaptic CB1 suppresses forskolin-mediated enhancement of synaptic transmission at the Pf-PC synapse, interfering with the AC1/PKA signaling cascade (107). Since previous in vitro studies reported possible interactions between AC1 and G-protein-coupled receptors (108), it is possible that eCB-mediated inhibition of prePf-LTP occurs via inhibition of AC1 by CB1coupled Gi protein. As we mentioned above, the physiological significance of mGluR4 autoreceptive function has been difficult to identify at Pf-PC synapses (89). However, analogous studies of other synapses suggest that mGluR4 activation can affect neurostransmitter release by modifying steps downstream of Ca2+ entry. At the calyx of Held synapse, modeling of the autoreceptor action of group III mGluRs following repetitive efferent stimulation suggests that the decrease in probability of release is associated with an increase in the readily releasable pool size (109). Thereby, the change in synapse state (increase in vesicle pool size) could hide the effect of mGluR activation on neurotransmission (decreased release probability), as the net excitatory postsynaptic current (EPSC) measured by electrophysiological recordings would be unchanged. Likewise in superior cervical ganglion neurons presynaptic mGluR4 has been shown to modulate short-term facilitation via a ligand-independent but Ca2+-dependent signaling mechanism affecting Munc18-1 activity (110). At basal Ca2+ concentration, Munc18-1 appears to be sequestered by mGluR4, preventing vesicle fusion and keeping neurotransmission at a low level. A rise in presynaptic Ca2+ following an action potential in the terminal could then induce calmodulinmediated liberation of Munc18-1 from mGluR4, and thereby facilitate synaptic transmission (110). Purinergic P2X and P2Y receptors have also been sugFunctional Neurology 2010; 25(3): 141-151
Presynaptic parallel fiber plasticity
gested to play a role in synaptic plasticity, even though the precise localization of these receptors has not yet been clearly identified in the cerebellar cortex (104). In cultured granule cells, several subtypes of ionotropic P2X and metabotropic P2Y receptors can activate the Ca2+/calmodulin kinase II (CaMKII) signaling pathway, positively modulating neurotransmitter release (111). Further investigations have shown that P2X7 receptor activation induces Ca2+ entry into granule cell terminals and phosphorylation of synapsin I by CaMKII (112,113). Immunohistochemical and in situ studies have reported expression of kainate receptor (KAR) subunits GluR5, GluR6 and KA2 in cerebellar granule cells (114,115), of which the GluR6 and KA2 subunits have been found in Pfs (116). Electrophysiological data obtained in mature granule cells confirmed that KARs can operate as functional autoreceptors (117). Moreover, Delaney et al. (118) demonstrated that agonist-mediated activation of presynaptic KARs reversely alters the strength of glutamatergic transmission at Pf-PC synapses, as well as transmission between Pfs and MLIs. Mimicking the physiological conditions of Pf stimulations, this bidirectional regulation of synaptic strength was shown to be dependent on the concentration of the agonist: low concentrations, corresponding to low-frequency stimulation, activate presynaptic KARs, whereas high concentrations of the same agonist reproduce high-frequency conditions and lead to KAR inhibition. In addition, the sensitivity to KAR activation at Pf-MLI synapses differs from that at Pf-PC synapses, as the dose-dependent activation of KARs is shifted to lower concentrations at PfMLI synapses (118).
Presynaptic action of nitric oxide Long-term potentiation of Pf-PC synapses may depend on NO production (48,49). Indeed, inhibition of NO synthase (85) prevents induction of Pf-PC potentiation, and inhibition of transcellular diffusion of NO blocks its spread to neighboring synapses (48). The source of NO at Pf terminals is not clear. The cellular distribution of NOS in the cerebellar cortex, as well as electrophysiological data, suggests that the Pfs themselves could produce NO (41,119), but it has also been suggested that activation of MLI NMDA receptors could be the source of NO release at Pf-PC synapses (49). It is generally accepted that NO regulates the probability of glutamate release primarily via cyclic guanosine monophosphate and protein kinase G-dependent mechanisms (120). However, the exact molecular mechanisms of NO presynaptic action at Pf-PC synapses are not clear yet, and it is uncertain whether the action of NO occurs downstream to that of cAMP (48) or whether it influences Ca2+ transients (49).
Proteosomal degradation of synaptic proteins Recently, degradation of synaptic proteins via the ubiquitin-proteasome system (UPS) (109) at both pre- and postsynaptic sites has been shown to be involved in synaptic plasticity and memory formation (121,122). E3 ligases are of particular importance in the UPS as they are responsible for the specific recognition of the target protein to be degraded. The tripartite motif protein 3 (TRIM3) has been shown to have an E3 ligase activity Functional Neurology 2010; 25(3): 141-151
mediated by its RING finger domain and to modulate synaptic plasticity at hippocampal synapses (123). In the cerebellum, TRIM3 is expressed by granule cells (Fig. 1), and TRIM3 knockout mice have shown some cerebellar learning deficits (123). Thus, it is likely that TRIM3-mediated proteosomal degradation can affect the turnover of some synaptic proteins involved in the vesicle release machinery, and thereby modulate glutamate release at Pf synapses.
Functional implications of presynaptic plasticity in parallel fibers The cerebellar cortex is able to compute multiple types of converging information in a fast, precise and efficient manner, thereby controlling motor performance and the formation of procedural memory (10,124). Granule cells are thought to be crucial in this process, because of their essential position in the cerebellar cortical circuitry as well as the great computational capacity allowed by their huge number and by their numerous connections with PCs (9). More specifically, the granular layer has been suggested to govern the temporal dynamics of cerebellar motor control due to the time-windowing effect of GC feedforward inhibition and the spike-coding of afferent signals determined by synaptic plasticity at granule cell synapses (10). Even though postsynaptic LTD has historically been thought to be the main mechanism underlying cerebellar motor learning (58), recent studies suggest that postsynaptic potentiation of Pf connections to PCs may be at least as important as LTD (14,35,125). The picture emerging from this review, in which we have surveyed the molecular and physiological ins and outs of the presynaptic forms of plasticity at the Pf-PC synapse, is that here too the dominant form of plasticity is probably potentiation. Even GABAa activation leads to potentiation and even those forms of presynaptic depression that are functional in Pf terminals, such as eCB-mediated suppression, occur mostly in a retrograde fashion; i.e. they appear to serve as an inhibitory control of the potentiation rather than a direct depression of the Pf. Thus, it appears that the Pf-PC synapse is bound to be potentiated, both post- and presynaptically, which suggests that these two forms of plasticity can team up for a behaviorally relevant function. Another important feature, which has already been pointed out by Linden (126), is that the range of mechanisms that may modulate glutamate release at the Pf synapses is enormous. The strength and nature of the signaling pathways of these presynaptic processes vary, depending on the Pf contacts with either PCs or interneurons (127), and the heterogeneity extends to the level of individual boutons of a single Pf (128). Moreover, even neighboring boutons of a single Pf that contact the same postsynaptic cell can show disparity in neuromodulator sensitivity (126). Therefore, even though potentiation may be the dominant direction, neurotransmission at Pfs appears to be regulated presynaptically at many different levels. Thus, the capacity to strengthen the Pf-PC synapse presynaptically in different ways endows the cerebellar cortex with optimal computational capabilities for potentiating wide-spectrum, spatial and temporal cues that are relevant for fine regulating of memory formation.
147
M.-C. Le Guen & C.I. De Zeeuw
References 1. Ramnani N. The primate cortico-cerebellar system: anatomy and function. Nat Rev Neurosci 2006;7:511-522 2. De Zeeuw CI, Koekkoek SK, van Alphen AM et al. Gain and phase control of compensatory eye movements by the flocculus of the vestibulo-cerebellum. In: Highstein SM ed Handbook of Auditory Research. New York; Springer 2004:375-422 3. Schmahmann JD. Disorders of the cerebellum: ataxia, dysmetria of thought, and the cerebellar cognitive affective syndrome. J Neuropsychiatry Clin Neurosci 2004;16:367-378 4. Manzoni D. The cerebellum and sensorimotor coupling: looking at the problem from the perspective of vestibular reflexes. Cerebellum 2007;6:24-37 5. Robinson FR, Fuchs AF. The role of the cerebellum in voluntary eye movements. Annu Rev Neurosci 2001;24:981-1004 6. Topka H, Konczak J, Schneider K, Boose A, Dichgans J. Multijoint arm movements in cerebellar ataxia: abnormal control of movement dynamics. Exp Brain Res 1998;119:493-503 7. Strick PL, Dum RP, Fiez JA. Cerebellum and nonmotor function. Annu Rev Neurosci 2009;32:413-434 8. Timmann D, Daum I. Cerebellar contributions to cognitive functions: a progress report after two decades of research. Cerebellum 2007;6:159-162 9. Voogd J, Glickstein M. The anatomy of the cerebellum. Trends Neurosci 1998;21:370-375 10. D’Angelo E, De Zeeuw CI. Timing and plasticity in the cerebellum: focus on the granular layer. Trends Neurosci 2009;32:30-40 11. Hansel C, Linden DJ, D’Angelo E. Beyond parallel fiber LTD: the diversity of synaptic and non-synaptic plasticity in the cerebellum. Nat Neurosci 2001;4:467-475 12. Evans GJ. Synaptic signalling in cerebellar plasticity. Biol Cell 2007;99:363-378 13. Ito M. Cerebellar long-term depression: characterization, signal transduction, and functional roles. Physiol Rev 2001;81:1143-1195 14. Schonewille M, Belmeguenai A, Koekkoek SK et al. Purkinje cell-specific knockout of the protein phosphatase PP2B impairs potentiation and cerebellar motor learning. Neuron 2010;67:618-628 15. Catterall WA, Few AP. Calcium channel regulation and presynaptic plasticity. Neuron 2008;59:882-901 16. Regehr WG, Carey MR, Best AR. Activity-dependent regulation of synapses by retrograde messengers. Neuron 2009;63:154-170 17. Sola E, Prestori F, Rossi P, Taglietti V, D’Angelo E. Increased neurotransmitter release during long-term potentiation at mossy fibre-granule cell synapses in rat cerebellum. J. Physiol 2004;557:843-861 18. Barbour B. Synaptic currents evoked in Purkinje cells by stimulating individual granule cells. Neuron 1993;11:759-769 19. Thach WT Jr. Somatosensory receptive fields of single units in cat cerebellar cortex. J Neurophysiol 1967;30:675-696 20. Manto M. The cerebellum, cerebellar disorders, and cerebellar research--two centuries of discoveries. Cerebellum 2008;7:505-516 21. Marr D. A theory of cerebellar cortex. J Physiol 1969; 202:437-470 22. Albus J. A theory of cerebellar function. Mathematical Bioscience 1971;volume??:10-61.
148
23. Chadderton P, Margrie TW, Häusser M. Integration of quanta in cerebellar granule cells during sensory processing. Nature 2004;428:856-860 24. Isope P, Dieudonné S, Barbour B. Temporal organization of activity in the cerebellar cortex: a manifesto for synchrony. Ann N Y Acad Sci 2002;978:164-174 25. D’Angelo E. The critical role of Golgi cells in regulating spatio-temporal integration and plasticity at the cerebellum input stage. Front Neurosci 2008;2:35-46 26. Robberechts Q, Wijnants M, Giugliano M, De Schutter E. Long-term depression at parallel fiber to Golgi cell synapses. J Neurophysiol 2010 Sep 22. [Epub ahead of print] 27. De Zeeuw CI, Hoebeek FE, Schonewille M. Causes and consequences of oscillations in the cerebellar cortex. Neuron 2008;58:655-658 28. D’Angelo E, Koekkoek SK, Lombardo P et al. Timing in the cerebellum: oscillations and resonance in the granular layer. Neuroscience 2009;162:805-815 29. Hartmann MJ, Bower JM. Oscillatory activity in the cerebellar hemispheres of unrestrained rats. J Neurophysiol 1998;80:1598-1604 30. Pellerin JP, Lamarre Y. Local field potential oscillations in primate cerebellar cortex during voluntary movement. J Neurophysiol 1997;78:3502-3507 31. Schnitzler A, Gross, J. Functional connectivity analysis in magnetoencephalography. Int Rev Neurobiol 2005;68: 173-195 32. O’Connor SM, Berg RW, Kleinfeld D. Coherent electrical activity between vibrissa sensory areas of cerebellum and neocortex is enhanced during free whisking. J Neurophysiol 2002;87:2137-2148 33. Courtemanche R, Pellerin JP, Lamarre Y. Local field potential oscillations in primate cerebellar cortex: modulation during active and passive expectancy. J Neurophysiol 2002;88:771-782 34. Kistler WM, De Zeeuw CI. Time windows and reverberating loops: a reverse-engineering approach to cerebellar function. Cerebellum 2003;2:44-54 35. Welsh JP, Yamaguchi H, Zeng XH et al. Normal motor learning during pharmacological prevention of Purkinje cell long-term depression. Proc Natl Acad Sci U S A 2005;102: 17166-17171 36. Hirano T. Differential pre- and postsynaptic mechanisms for synaptic potentiation and depression between a granule cell and a Purkinje cell in rat cerebellar culture. Synapse 1991;7:321-323 37. Hirano T. Depression and potentiation of the synaptic transmission between a granule cell and a Purkinje cell in rat cerebellar culture. Neurosci Lett 1990;119:141-144 38. Shibuki K, Okada D. Cerebellar long-term potentiation under suppressed postsynaptic Ca2+ activity. Neuroreport 1992;3:231-234 39. Salin PA, Malenka RC, Nicoll RA. Cyclic AMP mediates a presynaptic form of LTP at cerebellar parallel fiber synapses. Neuron 1996;16:797-803 40. Linden DJ. Synaptically evoked glutamate transport currents may be used to detect the expression of long-term potentiation in cerebellar culture. J Neurophysiol 1998;79:3151-3156 41. Kimura S, Uchiyama S, Takahashi HE, Shibuki K. cAMPdependent long-term potentiation of nitric oxide release from cerebellar parallel fibers in rats. J Neurosci 1998;18:8551-8558 42. Storm DR, Hansel C, Hacker B, Parent A, Linden DJ. Impaired cerebellar long-term potentiation in type I adenylyl cyclase mutant mice. Neuron 1998;20:1199-1210 Functional Neurology 2010; 25(3): 141-151
Presynaptic parallel fiber plasticity
43. Belmeguenai A, Hansel C. A role for protein phosphatases 1, 2A, and 2B in cerebellar long-term potentiation. J Neurosci 2005;25:10768-10772 44. Weisskopf MG, Castillo PE, Zalutsky RA, Nicoll RA. Mediation of hippocampal mossy fiber long-term potentiation by cyclic AMP. Science 1994;265:1878-1882 45. Castillo PE, Janz R, Südhof TC, Tzounopoulos T, Malenka RC, Nicoll RA. Rab3A is essential for mossy fibre longterm potentiation in the hippocampus. Nature 1997;388:590-593 46. Castillo PE, Schoch S, Schmitz F, Südhof TC, Malenka RC. RIM1alpha is required for presynaptic long-term potentiation. Nature 2002;415:327-330 47. Lonart G, Schoch S, Kaeser PS et al. Phosphorylation of RIM1alpha by PKA triggers presynaptic long-term potentiation at cerebellar parallel fiber synapses. Cell 2003;115:49-60 48. Jacoby S, Sims RE, Hartell NA. Nitric oxide is required for the induction and heterosynaptic spread of long-term potentiation in rat cerebellar slices. J Physiol 2001; 535:825-839 49. Qiu DL, Knöpfel T. An NMDA receptor/nitric oxide cascade in presynaptic parallel fiber-Purkinje neuron long-term potentiation. J Neurosci 2007;27:3408-3415 50. Zucker RS, Regehr WG. Short-term synaptic plasticity. Annu Rev Physiol 2002;64:355-405 51. Empson RM, Garside ML, Knöpfel T. Plasma membrane Ca2+ ATPase 2 contributes to short-term synapse plasticity at the parallel fiber to Purkinje neuron synapse. J Neurosci 2007;27:3753-3758 52. Beierlein M, Fioravante D, Regehr WG. Differential expression of posttetanic potentiation and retrograde signaling mediate target-dependent short-term synaptic plasticity. Neuron 2007;54:949-959 53. Brown SP, Brenowitz SD, Regehr WG. Brief presynaptic bursts evoke synapse-specific retrograde inhibition mediated by endogenous cannabinoids. Nat Neurosci 2003;6:1048-1057 54. Safo PK, Cravatt BF, Regehr WG. Retrograde endocannabinoid signaling in the cerebellar cortex. Cerebellum 2006;5:134-145 55. Brenowitz SD, Regehr WG. Associative short-term synaptic plasticity mediated by endocannabinoids. Neuron 2005;45:419-431 56. Goto J, Inoue T, Kuruma A, Mikoshiba K. Short-term potentiation at the parallel fiber-Purkinje cell synapse. Neurosci Res 2006;55:28-33 57. Bao J, Reim K, Sakaba T. Target-dependent feedforward inhibition mediated by short-term synaptic plasticity in the cerebellum. J Neurosci 2010;30:8171-8179 58. Beierlein M, Regehr WG. Local interneurons regulate synaptic strength by retrograde release of endocannabinoids. J Neurosci 2006;26:9935-9943 59. De Zeeuw CI. Plasticity: A pragmatic compromise. In: Roediger H, Dudai Y, Fitzpatrick, S eds Science of Memory: Concepts. New York; Oxford University Press 2007:83-86 60. Chavis P, Mollard P, Bockaert J, Manzoni O. Visualization of cyclic AMP-regulated presynaptic activity at cerebellar granule cells. Neuron 1998;20:773-781 61. Xia ZG, Refsdal CD, Merchant KM, Dorsa DM, Storm DR. Distribution of mRNA for the calmodulin-sensitive adenylate cyclase in rat brain: expression in areas associated with learning and memory. Neuron 1991;6:431-443 62. Linden DJ, Ahn S. Activation of presynaptic cAMP-dependent protein kinase is required for induction of cerebellar long-term potentiation. J Neurosci 1999;19: 10221-10227 Functional Neurology 2010; 25(3): 141-151
63. Schluter OM, Schnell E, Verhage M et al. Rabphilin knockout mice reveal that rabphilin is not required for rab3 function in regulating neurotransmitter release. J Neurosci 1999;19:5834-5846 64. Spillane DM, Rosahl TW, Südhof TC, Malenka RC. Longterm potentiation in mice lacking synapsins. Neuropharmacology 1995;34:1573-1579 65. Powell CM, Schoch S, Monteggia L et al. The presynaptic active zone protein RIM1alpha is critical for normal learning and memory. Neuron 2004;42:143-153 66. Simsek-Duran F, Linden DJ, Lonart G. Adapter protein 143-3 is required for a presynaptic form of LTP in the cerebellum. Nat Neurosci 2004;7:1296-1298 67. Kaeser PS, Kwon HB, Blundell J et al. RIM1alpha phosphorylation at serine-413 by protein kinase A is not required for presynaptic long-term plasticity or learning. Proc Natl Acad Sci U S A, 2008;105:14680-14685 68. Kreitzer AC, Regehr WG. Modulation of transmission during trains at a cerebellar synapse. J Neurosci 2000;20:1348-1357 69. Zhang CS, Bertaso F, Eulenburg V et al., Knock-in mice lacking the PDZ-ligand motif of mGluR7a show impaired PKC-dependent autoinhibition of glutamate release, spatial working memory deficits, and increased susceptibility to pentylenetetrazol. J Neurosci 2008;28:8604-8614 70. Kushner SA, Elgersma Y, Murphy GG et al. Modulation of presynaptic plasticity and learning by the H-ras/extracellular signal-regulated kinase/synapsin I signaling pathway. J Neurosci 2005;25:9721-9734 71. Woolf CJ, MaQ. Nociceptors - noxious stimulus detectors. Neuron 2007;55:353-364 72. Heifets BD, Castillo PE. Endocannabinoid signaling and longterm synaptic plasticity. Annu Rev Physiol 2009;71:283-306 73. Herkenham M, Lynn AB, Johnson MR, Melvin LS, de Costa BR, Rice KC. Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J Neurosci 1991;11:563-583 74. Tsou K, Brown S, Sañudo-Peña MC, Mackie K, Walker JM. Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience 1998;83:393-411 75. Levenes C, Daniel H, Soubrié P, Crépel F. Cannabinoids decrease excitatory synaptic transmission and impair longterm depression in rat cerebellar Purkinje cells. J Physiol 1998;510: 867-879 76. Kreitzer AC, Regehr WG. Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells. Neuron 2001;29:717-727 77. Maejima T, Hashimoto K, Yoshida T, Aiba A, Kano M. Presynaptic inhibition caused by retrograde signal from metabotropic glutamate to cannabinoid receptors. Neuron 2001;31:463-475 78. Safo PK, Regehr WG. Endocannabinoids control the induction of cerebellar LTD. Neuron 2005;48:647-659 79. Maejima T, Oka S, Hashimotodani Y et al. Synaptically driven endocannabinoid release requires Ca2+-assisted metabotropic glutamate receptor subtype 1 to phospholipase Cbeta4 signaling cascade in the cerebellum. J Neurosci 2005;25:6826-6835 80. Brown SP, Safo PK, Regehr WG. Endocannabinoids inhibit transmission at granule cell to Purkinje cell synapses by modulating three types of presynaptic calcium channels. J Neurosci 2004;24:5623-5631 81. Kishimoto Y, Kano M. Endogenous cannabinoid signaling through the CB1 receptor is essential for cerebellum-dependent discrete motor learning. J Neurosci 2006;26:8829-8837
149
M.-C. Le Guen & C.I. De Zeeuw
82. Iacovelli L, Bruno V, Salvatore L et al. Native group-III metabotropic glutamate receptors are coupled to the mitogen-activated protein kinase/phosphatidylinositol-3-kinase pathways. J Neurochem 2002;82:216-223 83. Tanabe Y, Nomura A, Masu M, Shigemoto R, Mizuno N, Nakanishi S. Signal transduction, pharmacological properties, and expression patterns of two rat metabotropic glutamate receptors, mGluR3 and mGluR4. J Neurosci 1993;13:1372-1378 84. Berthele A, Platzer S, Laurie DJ et al. Expression of metabotropic glutamate receptor subtype mRNA (mGluR1-8) in human cerebellum. Neuroreport 1999;10:3861-3867 85. Kinoshita A, Ohishi H, Nomura S, Shigemoto R, Nakanishi S, Mizuno N. Presynaptic localization of a metabotropic glutamate receptor, mGluR4a, in the cerebellar cortex: a light and electron microscope study in the rat. Neurosci Lett 1996;207:199-202 86. Mateos JM, Elezgarai I, Benítez R et al. Clustering of the group III metabotropic glutamate receptor 4a at parallel fiber synaptic terminals in the rat cerebellar molecular layer. Neurosci Res 1999;35:71-74 87. Pekhletski R, Gerlai R, Overstreet LS et al. Impaired cerebellar synaptic plasticity and motor performance in mice lacking the mGluR4 subtype of metabotropic glutamate receptor. J Neurosci 1996;16:6364-6373 88. Neale SA, Garthwaite J, Batchelor AM. Metabotropic glutamate receptor subtypes modulating neurotransmission at parallel fibre-Purkinje cell synapses in rat cerebellum. Neuropharmacology 2001;41:42-49 89. Lorez M, Humbel U, Pflimlin MC, Kew JN. Group III metabotropic glutamate receptors as autoreceptors in the cerebellar cortex. Br J Pharmacol 2003;138:614-625 90. Abitbol K, Acher F, Daniel H. Depression of excitatory transmission at PF-PC synapse by group III metabotropic glutamate receptors is provided exclusively by mGluR4 in the rodent cerebellar cortex. J Neurochem 2008;105:2069-2079 91. Daniel H, Crepel F. Control of Ca(2+) influx by cannabinoid and metabotropic glutamate receptors in rat cerebellar cortex requires K(+) channels. J Physiol 2001;537:793-800 92. Bowery NG, Hill DR, Hudson AL. Characteristics of GABAB receptor binding sites on rat whole brain synaptic membranes. Br J Pharmacol 1983;78:191-206 93. Wojcik WJ, Neff NH. gamma-aminobutyric acid B receptors are negatively coupled to adenylate cyclase in brain, and in the cerebellum these receptors may be associated with granule cells. Mol Pharmacol 1984;25:24-28 94. Bowery NG, Hudson AL, Price GW. GABAA and GABAB receptor site distribution in the rat central nervous system. Neuroscience 1987;20:365-383 95. Chu DC, Albin RL, Young AB, Penney JB. Distribution and kinetics of GABAB binding sites in rat central nervous system: a quantitative autoradiographic study. Neuroscience 1990;34:341-357 96. Billinton A, Upton N, Bowery NG. GABA(B) receptor isoforms GBR1a and GBR1b, appear to be associated with pre- and post-synaptic elements respectively in rat and human cerebellum. Br J Pharmacol 1999;126:1387-1392 97. Dittman JS, Regehr WG. Contributions of calcium-dependent and calcium-independent mechanisms to presynaptic inhibition at a cerebellar synapse. J Neurosci 1996;16:1623-1633 98. Dittman JS, Regehr WG. Mechanism and kinetics of heterosynaptic depression at a cerebellar synapse. J Neurosci 1997;17:9048-9059
150
99. Goodman RR, Kuhar MJ, Hester L, Snyder SH. Adenosine receptors: autoradiographic evidence for their location on axon terminals of excitatory neurons. Science 1983;220:967-969 100. Rivkees SA, Price SL, Zhou FC. Immunohistochemical detection of A1 adenosine receptors in rat brain with emphasis on localization in the hippocampal formation, cerebral cortex, cerebellum, and basal ganglia. Brain Res 1995;677:193-203 101. Kocsis JD, Eng DL, Bhisitkul RB. Adenosine selectively blocks parallel-fiber-mediated synaptic potentials in rat cerebellar cortex. Proc Natl Acad Sci U S A 1984;81:6531-6534 102. Takahashi M, Kovalchuk Y, Attwell D. Pre- and postsynaptic determinants of EPSC waveform at cerebellar climbing fiber and parallel fiber to Purkinje cell synapses. J Neurosci 1995;15:5693-5702 103. Wall MJ, Dale N. Auto-inhibition of rat parallel fibre-Purkinje cell synapses by activity-dependent adenosine release. J Physiol 2007;581:553-565 104. Courjaret R, Miras-Portugal MT, Deitmer JW. Purinergic modulation of granule cells. Cerebellum 2010 Aug 6. [Epub ahead of print] 105. Wall M, Dale N. Activity-dependent release of adenosine: a critical re-evaluation of mechanism. Curr Neuropharmacol 2008;6:329-337 106. Stell BM, Rostaing P, Triller A, Marty A. Activation of presynaptic GABA(A) receptors induces glutamate release from parallel fiber synapses. J Neurosci 2007;27:9022-9031 107. van Beugen BJ, Nagaraja RY, Hansel C. Climbing fiberevoked endocannabinoid signaling heterosynaptically suppresses presynaptic cerebellar long-term potentiation. J Neurosci 2006;26:8289-8294 108. Wayman GA, Impey S, Wu Z, Kindsvogel W, Prichard L, Storm DR. Synergistic activation of the type I adenylyl cyclase by Ca2+ and Gs-coupled receptors in vivo. J Biol Chem 1994;269:25400-25405 109. Billups B, Graham BP, Wong AY, Forsythe ID. Unmasking group III metabotropic glutamate autoreceptor function at excitatory synapses in the rat CNS. J Physiol 2005;565:885-896 110. Nakajima Y, Mochida S, Okawa K, Nakanishi S. Ca2+-dependent release of Munc18-1 from presynaptic mGluRs in short-term facilitation. Proc Natl Acad Sci U S A 2009;106:18385-18389 111. Leon D, Hervás C, Miras-Portugal MT. P2Y1 and P2X7 receptors induce calcium/calmodulin-dependent protein kinase II phosphorylation in cerebellar granule neurons. Eur J Neurosci 2006;23:2999-3013 112. León D, Sánchez-Nogueiro J, Marín-García P, Miras-Portugal MA. Glutamate release and synapsin-I phosphorylation induced by P2X7 receptors activation in cerebellar granule neurons. Neurochem Int 2008;52:1148-1159 113. Sánchez-Nogueiro J, Marín-García P, León D et al. Axodendritic fibres of mouse cerebellar granule neurons exhibit a diversity of functional P2X receptors. Neurochem Int 2009;55:671-682 114. Bahn S, Volk B, Wisden W. Kainate receptor gene expression in the developing rat brain. J Neurosci 1994;14:5525-5547 115. Herb A, Burnashev N, Werner P et al. The KA-2 subunit of excitatory amino acid receptors shows widespread expression in brain and forms ion channels with distantly related subunits. Neuron 1992;8:775-785 116. Petralia RS, Wang YX, Wenthold RJ. Histological and ultrastructural localization of the kainate receptor subunits, KA2 and GluR6/7, in the rat nervous system using selective antipeptide antibodies. J Comp Neurol 1994;349:85-110 Functional Neurology 2010; 25(3): 141-151
Presynaptic parallel fiber plasticity
117. Smith TC, Wang LY, Howe JR. Distinct kainate receptor phenotypes in immature and mature mouse cerebellar granule cells. J Physiol 1999;517: 51-58 118. Delaney AJ, Jahr CE. Kainate receptors differentially regulate release at two parallel fiber synapses. Neuron 2002;36:475-482 119. Southam E, Morris R, Garthwaite J. Sources and targets of nitric oxide in rat cerebellum. Neurosci Lett 1992;13:241-244 120. Feil R, Kleppisch T. NO/cGMP-dependent modulation of synaptic transmission. In: Südhof T, Starke K eds Pharmacology of Neurotransmitter Release. Berlin; Springer. 2008:529-560 121. Haas KF, Broadie K. Roles of ubiquitination at the synapse. Biochim Biophys Acta 2008;1779:495-506 122. Tai HC, Schuman EM. Ubiquitin, the proteasome and protein degradation in neuronal function and dysfunction. Nat Rev Neurosci 2008;9:826-838
Functional Neurology 2010; 25(3): 141-151
123. Vegh M, Van Diepen M, Groffen A et al. Role of Tripartite (TRIM) RING finger proteins in synaptic plasticity. FENS Abstr 2010. 5(043.58) 124. De Zeeuw CI, Yeo CH. Time and tide in cerebellar memory formation. Curr Opin Neurobiol 2005;15:667-674 125. Dean P, Porrill J. Adaptive-filter models of the cerebellum: computational analysis. Cerebellum 2008;7:567-571 126. Zhang W, Linden DJ. Neuromodulation at single presynaptic boutons of cerebellar parallel fibers is determined by bouton size and basal action potential-evoked Ca transient amplitude. J Neurosci 2009;29:15586-15594 127. Koester HJ, Johnston D. Target cell-dependent normalization of transmitter release at neocortical synapses. Science 2005;308:863-866 128. Brenowitz SD, Regehr WG. Reliability and heterogeneity of calcium signaling at single presynaptic boutons of cerebellar granule cells. J Neurosci 2007;27:7888-7898
151