Parallel Fiber Synapses Research Articles

Presynaptically Expressed Long-Term Potentiation Increases Multivesicular Release at Parallel Fiber Synapses

At a number of synapses, long-term potentiation (LTP) can be expressed by an increase in presynaptic strength, but it is unknown whether presynaptic LTP is expressed solely through an increase in the probability that a single vesicle is released or whether it can increase multivesicular release (MVR). Here, we show that presynaptic LTP decreases inhibition of AMPA receptor EPSCs by a low-affinity antagonist at parallel fiber-molecular layer interneuron (PF-MLI) synapses. This indicates that LTP induction results in larger glutamate concentration transients in the synaptic cleft, a result indicative of MVR, and suggests that MVR can be modified by long-term plasticity. A similar decrease in inhibition was observed when release probability (PR) was increased by forskolin, elevated extracellular Ca2+, and paired-pulse facilitation. Furthermore, we show that MVR may occur under baseline physiological conditions, as inhibition increased when P(R) was lowered by reducing extracellular Ca2+ or by activating presynaptic adenosine receptors. These results suggest that at PF-MLI synapses, MVR occurs under control conditions and is increased when PR is elevated by both short- and long-term plasticity mechanisms.

Functions of glutamate transporters in cerebellar Purkinje cell synapses

Glutamate transporters play a critical role in the maintenance of low extracellular concentrations of glutamate, which prevents the overactivation of post-synaptic glutamate receptors. Four distinct glutamate transporters, GLAST/EAAT1, GLT-1/EAAT2, EAAC1/EAAT3 and EAAT4, are distributed in the molecular layer of the cerebellum, especially near glutamatergic synapses in Purkinje cells (PCs). This review summarizes the current knowledge about the differential roles of these transporters at excitatory synapses of PCs. Data come predominantly from electrophysiological experiments in mutant mice that are deficient in each of these transporter genes. GLAST expressed in Bergmann glia contributes to the clearing of the majority of glutamate that floods out of the synaptic cleft immediately after transmitter release from the climbing fibre (CF) and parallel fibre (PF) terminals. It is indispensable to maintain a one-to-one relationship in synaptic transmission at the CF synapses by preventing transcellular glutamate spillover. GLT-1 plays a similar but minor role in the uptake of glutamate as GLAST. Although the loss of neither GLAST nor GLT-1 affects cerebellar morphology, the deletion of both GLAST and GLT-1 genes causes the death of the mutant animal and hinders the folium formation of the cerebellum. EAAT4 removes the low concentrations of glutamate that escape from uptake by glial transporters, preventing the transmitter from spilling over into neighbouring synapses. It also regulates the activation of metabotropic glutamate receptor 1 (mGluR1) in perisynaptic regions at PF synapses, which in turn affects mGluR1-mediated events including slow EPSCs and long-term depression. No change in synaptic function is detected in mice that are deficient in EAAC1.

Two Distinct Types of Inhibition Mediated by Cartwheel Cells in the Dorsal Cochlear Nucleus

Individual neurons have been shown to exhibit target cell-specific synaptic function in several brain areas. The time course of the postsynaptic conductances (PSCs) strongly influences the dynamics of local neural networks. Cartwheel cells (CWCs) are the most numerous inhibitory interneurons in the dorsal cochlear nucleus (DCN). They are excited by parallel fiber synapses, which carry polysensory information, and in turn inhibit other CWCs and the main projection neurons of the DCN, pyramidal cells (PCs). CWCs have been implicated in "context-dependent" inhibition, producing either depolarizing (other CWCs) or hyperpolarizing (PCs) post synaptic potentials. In the present study, we used paired whole cell recordings to examine target-dependent inhibition from CWCs in neonatal rat DCN slices. We found that CWC inhibitory postsynaptic potentials (IPSPs) onto PCs are large (1.3 mV) and brief (half-width = 11.8 ms), whereas CWC IPSPs onto other CWCs are small (0.2 mV) and slow (half-width = 36.8 ms). Evoked IPSPs between CWCs exhibit paired-pulse facilitation, while CWC IPSPs onto PCs exhibit paired-pulse depression. Perforated-patch recordings showed that spontaneous IPSPs in CWCs are hyperpolarizing at rest with a mean estimated reversal potential of -67 mV. Spontaneous IPSCs were smaller and lasted longer in CWCs than in PCs, suggesting that the kinetics of the receptors are different in the two cell types. These results reveal that CWCs play a dual role in the DCN. The CWC-CWC network interactions are slow and sensitive to the average rate of CWC firing, whereas the CWC-PC network is fast and sensitive to transient changes in CWC firing.

The N-Terminal Domain of GluD2 (GluRδ2) Recruits Presynaptic Terminals and Regulates Synaptogenesis in the CerebellumIn Vivo

The delta2 glutamate receptor (GluRdelta2; GluD2), which is predominantly expressed on postsynaptic sites at parallel fiber (PF)-Purkinje cell synapses in the cerebellum, plays two crucial roles in the cerebellum: the formation of PF synapses and the regulation of long-term depression (LTD), a form of synaptic plasticity underlying motor learning. Although the induction of LTD and motor learning absolutely require signaling via the cytoplasmic C-terminal domain of GluD2, the mechanisms by which GluD2 regulates PF synaptogenesis have remained unclear. Here, we examined the role of the extracellular N-terminal domain (NTD) of GluD2 on PF synaptogenesis by injecting Sindbis virus carrying wild-type (GluD2(wt)) or mutant GluD2 into the subarachnoid supracerebellar space of GluD2-null mice. Remarkably, the expression of GluD2(wt), but not of a mutant GluD2 lacking the NTD (GluD2(DeltaNTD)), rapidly induced PF synapse formation and rescued gross motor dyscoordination in adult GluD2-null mice just 1 d after injection. In addition, although the kainate receptor GluR6 (GluK2) did not induce PF synaptogenesis, a chimeric GluK2 that contained the NTD of GluD2 (GluD2(NTD)-GluK2) did. Similarly, GluD2(wt) and GluD2(NTD)-GluK2, but not GluD2(DeltaNTD), induced synaptogenesis in heterologous cells in vitro. In contrast, LTD was restored in GluD2-null Purkinje cells expressing a mutant GluD2 lacking the NTD. These results indicate that the NTD of GluD2 is necessary and sufficient for the function of GluD2 in the regulation of PF-Purkinje cell synaptogenesis. Furthermore, our results suggest that GluD2 differently regulates PF synaptogenesis and cerebellar LTD through the extracellular NTD and the cytoplasmic C-terminal end, respectively.

Learning to Encode Timing: Mechanisms of Plasticity in the Auditory Brainstem

Mechanisms of plasticity have traditionally been ascribed to higher-order sensory processing areas such as the cortex, whereas early sensory processing centers have been considered largely hard-wired. In agreement with this view, the auditory brainstem has been viewed as a nonplastic site, important for preserving temporal information and minimizing transmission delays. However, recent groundbreaking results from animal models and human studies have revealed remarkable evidence for cellular and behavioral mechanisms for learning and memory in the auditory brainstem.

Reading the Clock: How Purkinje Cells Decode the Phase of Olivary Oscillations

Climbing fiber responses in cerebellar Purkinje cells are described as being invariant. In this issue of Neuron, Mathy et al. show that the complex spike waveform changes with the number of spikes in a climbing fiber burst, which depends on the phase of olivary oscillations. In turn, different complex spike profiles affect synaptic plasticity at parallel fiber synapses. Thus, information on inferior olive oscillation states is reflected in both the complex spike waveform and the parallel fiber input gain.

Encoding of Oscillations by Axonal Bursts in Inferior Olive Neurons

SummaryInferior olive neurons regulate plasticity and timing in the cerebellar cortex via the climbing fiber pathway, but direct characterization of the output of this nucleus has remained elusive. We show that single somatic action potentials in olivary neurons are translated into a burst of axonal spikes. The number of spikes in the burst depends on the phase of subthreshold oscillations and, therefore, encodes the state of the olivary network. These bursts can be successfully transmitted to the cerebellar cortex in vivo, having a significant impact on Purkinje cells. They enhance dendritic spikes, modulate the complex spike pattern, and promote short-term and long-term plasticity at parallel fiber synapses in a manner dependent on the number of spikes in the burst. Our results challenge the view that the climbing fiber conveys an all-or-none signal to the cerebellar cortex and help to link learning and timing theories of olivocerebellar function.

Synaptic mGluR activation drives plasticity of calcium-permeable AMPA receptors

In contrast with conventional NMDA receptor-dependent synaptic plasticity, the synaptic events controlling the plasticity of GluR2-lacking Ca(2+)-permeable AMPA receptors (CP-AMPARs) remain unclear. At parallel fiber synapses onto cerebellar stellate cells, Ca(2+) influx through AMPARs triggers a switch in AMPAR subunit composition, resulting in loss of Ca(2+) permeabilty. Paradoxically, synaptically induced depolarization will suppress this Ca(2+) entry by promoting polyamine block of CP-AMPARs. We therefore examined other mechanisms that may control this receptor regulation under physiological conditions. We found that activation of both mGluRs and CP-AMPARs is necessary and sufficient to drive an AMPAR subunit switch and that by enhancing mGluR activity, GABA(B)R activation promotes this plasticity. Furthermore, we found that mGluRs and GABA(B)Rs are tonically activated, thus setting the basal tone for EPSC amplitude and rectification. Regulation by both excitatory and inhibitory inputs provides an unexpected mechanism that determines the potential of these synapses to show dynamic changes in AMPAR Ca(2+) permeability.

3D electron microscopic reconstruction of segments of rat cerebellar purkinje cell dendrites receiving ascending and parallel fiber granule cell synaptic inputs

Growing physiological evidence suggests that there are functional differences between synapses made by the ascending and parallel fiber segments of the granule axon on cerebellar Purkinje cells. Supporting this view, our previous electron microscopic studies suggested that these synapses also contacted different regions of the Purkinje cell dendrite, and in particular that ascending segment synapses are made exclusively on the smallest diameter Purkinje cell dendrites. In the current study we used serial electron microscopic techniques to reconstruct Purkinje cell dendritic segments up to almost 10 mum in length. Using a combination of anatomical and immunological labeling techniques we identified the ascending or parallel fiber origins of the excitatory synaptic inputs onto dendritic spines, as well as the location of inhibitory synapses made directly on the dendritic shaft. The results confirmed that there are regions of the Purkinje cell dendrite receiving exclusively ascending or parallel fiber synapses and that ascending segment synapses are only found on small-diameter dendrites. In addition, we describe for the first time small-diameter dendritic regions contacted by both types of excitatory synapses. While our data suggest that the majority of inhibitory inputs to the Purkinje cell tree are associated with parallel fiber synaptic inputs, we also found inhibitory inputs on dendritic regions with mixed ascending and parallel fiber inputs, or exclusively parallel fiber inputs. The finding that ascending and parallel fiber inputs can be segregated on the Purkinje cell dendritic tree provides further evidence that these excitatory granule cell synaptic inputs may be functionally distinct.

Distinct Functional and Anatomical Architecture of the Endocannabinoid System in the Auditory Brainstem

Endocannabinoids (ECs) act as retrograde messengers that enable postsynaptic cells to regulate the strength of their synaptic inputs. Here, by using physiological and histological techniques, we showed that, unlike in other parts of the brain, excitatory inputs are more sensitive than inhibitory inputs to EC signaling in the dorsal cochlear nucleus (DCN), an auditory brainstem nucleus. The principal cells of the DCN, fusiform cells, integrate acoustic signals through nonplastic synapses located in the deep layer with multimodal sensory signals carried by plastic parallel fibers in the molecular layer. Parallel fibers contact fusiform cells and inhibitory interneurons, the cartwheel cells, which in turn inhibit fusiform cells. Postsynaptic depolarization or pairing of postsynaptic potentials (PSPs) with action potentials (APs) induced EC-mediated modulation of excitatory inputs but did not affect inhibitory inputs. Quantitative electron microscopical studies showed that glutamatergic terminals express more cannabinoid 1 receptors (CB1Rs) than glycinergic terminals. Fusiform and cartwheel cells express diacylglycerol lipase alpha and beta (DGLalpha/beta), the two enzymes involved in the generation of the EC, 2-arachidonoyl-glycerol (2-AG). DGLalpha and DGLbeta are found in the spines of cartwheel but not fusiform cells indicating that the synthesis of ECs is more distant from parallel fiber synapses in fusiform than cartwheel cells. The differential localization and density of DGLalpha/beta and CB1Rs leads to cell- and input-specific EC signaling that favors activity-dependent EC-mediated suppression at synapses between parallel fibers and cartwheel cell spines, thus leading to reduced feedforward inhibition in fusiform cells. We propose that EC signaling is a major modulator of the balance of excitation and inhibition in auditory circuits.

Cbln1 binds to specific postsynaptic sites at parallel fiber–Purkinje cell synapses in the cerebellum

Cbln1, which belongs to the C1q/tumor necrosis factor superfamily, is a unique molecule that is not only required for maintaining normal parallel fiber (PF)-Purkinje cell synapses, but is also capable of inducing new PF synapses in adult cerebellum. Although Cbln1 is reportedly released from granule cells, where and how Cbln1 binds in the cerebellum has remained largely unclear, partly because Cbln1 undergoes proteolysis to yield various fragments that are differentially detected by different antibodies. To circumvent this problem, we characterized the Cbln1-binding site using recombinant Cbln1. An immunohistochemical analysis revealed that recombinant Cbln1 preferentially bound to PF-Purkinje cell synapses in primary cultures and acute slice preparations in a saturable and replaceable manner. Specific binding was observed for intact Cbln1 that had formed a hexamer, but not for the N-terminal or C-terminal fragments of Cbln1 fused to other proteins. Similarly, mutant Cbln1 that had formed a trimer did not bind to the Purkinje cells. Immunoreactivity for the recombinant Cbln1 was observed in weaver cerebellum (which lacks granule cells) but was absent in pcd cerebellum (which lacks Purkinje cells), suggesting that the binding site was located on the postsynaptic sites of PF-Purkinje cell synapses. Finally, a subcellular fractionation analysis revealed that recombinant Cbln1 bound to the synaptosomal and postsynaptic density fractions. These results indicate that Cbln1, released from granule cells as hexamers, specifically binds to a putative receptor located at the postsynaptic sites of PF-Purkinje cell synapses, where it induces synaptogenesis.

Climbing fiber signaling and cerebellar gain control

The physiology of climbing fiber signals in cerebellar Purkinje cells has been studied since the early days of electrophysiology. Both the climbing fiber-evoked complex spike and the role of climbing fiber activity in the induction of long-term depression (LTD) at parallel fiber-Purkinje cell synapses have become hallmark features of cerebellar physiology. However, the key role of climbing fiber signaling in cerebellar motor learning has been challenged by recent reports of forms of synaptic and non-synaptic plasticity in the cerebellar cortex that do not involve climbing fiber activity, but might well play a role in cerebellar learning. Moreover, cerebellar LTD does not seem to strictly require climbing fiber activity. These observations make it necessary to re-evaluate the role of climbing fiber signaling in cerebellar function. Here, we argue that climbing fiber signaling is about adjusting relative probabilities for the induction of LTD and long-term potentiation (LTP) at parallel fiber synapses. Complex spike-associated, dendritic calcium transients control postsynaptic LTD and LTP induction. High calcium transients, provided by complex spike activity, do not only favor postsynaptic LTD induction, but simultaneously trigger retrograde cannabinoid signaling, which blocks the induction of presynaptic LTP. Plasticity of the climbing fiber input itself provides additional means to fine-tune complex spike associated calcium signaling and thus to adjust the gain of heterosynaptic climbing fiber control. In addition to dendritic calcium transients, climbing fiber activity leads to the release of the neuropeptide corticotropin-releasing factor (CRF), which facilitates LTD induction at both parallel fiber and climbing fiber synapses.

Dendritic Spike Saturation of Endogenous Calcium Buffer and Induction of Postsynaptic Cerebellar LTP

The architecture of parallel fiber axons contacting cerebellar Purkinje neurons retains spatial information over long distances. Parallel fiber synapses can trigger local dendritic calcium spikes, but whether and how this calcium signal leads to plastic changes that decode the parallel fiber input organization is unknown. By combining voltage and calcium imaging, we show that calcium signals, elicited by parallel fiber stimulation and mediated by voltage-gated calcium channels, increase non-linearly during high-frequency bursts of electrically constant calcium spikes, because they locally and transiently saturate the endogenous buffer. We demonstrate that these non-linear calcium signals, independently of NMDA or metabotropic glutamate receptor activation, can induce parallel fiber long-term potentiation. Two-photon imaging in coronal slices revealed that calcium signals inducing long-term potentiation can be observed by stimulating either the parallel fiber or the ascending fiber pathway. We propose that local dendritic calcium spikes, evoked by synaptic potentials, provide a unique mechanism to spatially decode parallel fiber signals into cerebellar circuitry changes.

Differential modulation of cerebellar climbing fiber and parallel fiber synaptic responses at high pressure

High pressure, which induces central nervous system (CNS) dysfunction (high-pressure neurological syndrome) depresses synaptic transmission at all synapses examined to date. Several lines of evidence indicate an inhibitory effect of pressure on Ca(2+) entry into the presynaptic terminal. In the present work we studied for the first time the effect of pressure on the cerebellar climbing fiber (CF) synaptic responses. Pressure modulation of cerebellar synaptic plasticity was tested in both the CF and parallel fiber (PF) pathways using paired-pulse protocols. CF synapses, which normally operate at a high baseline release probability, demonstrate paired-pulse depression (PPD). High pressure reduced CF synaptic responses at 5.1 and 10.1 MPa but did not affect its PPD. High extracellular Ca(2+) concentration ([Ca(2+)](o)) could not antagonize the effect of pressure on the CF response, whereas low [Ca(2+)](o), in contrast to pressure, decreased both the response amplitude and the observed PPD. PF synapses, which usually operate at low release probability, exhibit paired-pulse facilitation (PPF). Pressure increased PF PPF at all interstimulus intervals (ISIs) tested (20-200 ms). Several Ca(2+) channel blockers as well as low [Ca(2+)](o) could mimic the effect of pressure on the PF response but significantly increased the PPF only at the 20-ms ISI. These results, together with previous data, show that the CF synapse is relatively resistant to pressure. The lack of pressure effect on CF PPD is surprising and may suggest that the PPD is not directly linked to synaptic depletion, as generally suggested. The increase in PPF of the PF at pressure, which is mimicked by Ca(2+) channel blockers or low [Ca(2+)](o), further supports pressure involvement in synaptic release mechanism(s). These results also indicate that pressure effects may be selective for various types of synapses in the CNS.

Formation and maturation of parallel fiber‐purkinje cell synapses in the staggerer cerebellum ex vivo

In vivo, homozygous staggerer (Rora(sg/sg)) Purkinje cells (PCs) remain in an early stage of development with rudimentary spineless dendrites, associated with a lack of parallel fiber (PF) input and the persistence of multiple climbing fibers (CFs). In this immunocytochemical study we used cerebellar organotypic cultures to monitor the development of Rora(sg/sg) PF-PC synapses in the absence of CF innervation. Ex vivo the vesicular glutamate transporters VGluT1 and VGluT2 reactivity was preferentially localized around the Rora(sg/sg) PC soma and proximal dendrites, which are typically CF domains. The shift from VGluT2 to VGluT1 in PF terminals during development was delayed in Rora(sg/sg) slices. The postsynaptic receptors mGluR1 and GluRdelta2 were differently distributed on Rora(sg/sg) PCs. mGluR1 reactivity was evenly distributed in PC soma and dendrites, whereas GluRdelta2 reactivity, normally restricted at PF synapses, was dense in Rora(sg/sg) PC somata. The presynaptic distribution of VGluT1 and VGluT2 on Rora(sg/sg) PCs matched the postsynaptic distribution of the glutamate receptor GluRdelta2, but not mGluR1.

Adaptive-filter Models of the Cerebellum: Computational Analysis

Many current models of the cerebellar cortical microcircuit are equivalent to an adaptive filter using the covariance learning rule. The adaptive filter is a development of the original Marr-Albus framework that deals naturally with continuous time-varying signals, thus addressing the issue of 'timing' in cerebellar function, and it can be connected in a variety of ways to other parts of the system, consistent with the microzonal organization of cerebellar cortex. However, its computational capacities are not well understood. Here we summarise the results of recent work that has focused on two of its intrinsic properties. First, an adaptive filter seeks to decorrelate its (mossy fibre) inputs from a (climbing fibre) teaching signal. This procedure can be used both for sensory processing, e.g. removal of interference from sensory signals, and for learning accurate motor commands, by decorrelating an efference copy of those commands from a sensory signal of inaccuracy. As a model of the cerebellum the adaptive filter thus forms a natural link between events at the cellular level, such as forms of synaptic plasticity and the learning rules they embody, and intelligent behaviour at the system level. Secondly, it has been shown that the covariance learning rule enables the filter to handle input and intrinsic noise optimally. Such optimality may underlie the recently described role of the cerebellum in producing accurate smooth pursuit eye movements in the face of sensory noise. Moreover, it has the consequence of driving most input weights to very small values, consistent with experimental data that many parallel-fibre synapses are normally silent. The effectiveness of silent synapses can only be altered by LTP, so learning tasks depending on a reduction of Purkinje cell firing require the synapses to be embedded in a second, inhibitory pathway from parallel fibre to Purkinje cell. This pathway and the appropriate climbing-fibre related plasticity have been described experimentally, and its presence has implications for asymmetries and hysteresis in behavioural learning rates that are also consistent with experimental observations. These computational properties of the adaptive filter suggest that it is both powerful and realistic enough to be a suitable candidate model of the cerebellar cortical microcircuit.

Alcohol Impairs Long-Term Depression at the Cerebellar Parallel Fiber–Purkinje Cell Synapse

Acute alcohol consumption causes deficits in motor coordination and gait, suggesting an involvement of cerebellar circuits, which play a role in the fine adjustment of movements and in motor learning. It has previously been shown that ethanol modulates inhibitory transmission in the cerebellum and affects synaptic transmission and plasticity at excitatory climbing fiber (CF) to Purkinje cell synapses. However, it has not been examined thus far how acute ethanol application affects long-term depression (LTD) and long-term potentiation (LTP) at excitatory parallel fiber (PF) to Purkinje cell synapses, which are assumed to mediate forms of cerebellar motor learning. To examine ethanol effects on PF synaptic transmission and plasticity, we performed whole cell patch-clamp recordings from Purkinje cells in rat cerebellar slices. We found that ethanol (50 mM) selectively blocked PF-LTD induction, whereas it did not change the amplitude of excitatory postsynaptic currents at PF synapses. In contrast, ethanol application reduced voltage-gated calcium currents and type 1 metabotropic glutamate receptor (mGluR1)-dependent responses in Purkinje cells, both of which are involved in PF-LTD induction. The selectivity of these effects is emphasized by the observation that ethanol did not impair PF-LTP and that PF-LTP could readily be induced in the presence of the group I mGluR antagonist AIDA or the mGluR1a antagonist LY367385. Taken together, these findings identify calcium currents and mGluR1-dependent signaling pathways as potential ethanol targets and suggest that an ethanol-induced blockade of PF-LTD could contribute to the motor coordination deficits resulting from alcohol consumption.

Adaptive processing in electrosensory systems: Links to cerebellar plasticity and learning

The first central stage of electrosensory processing in fish takes place in structures with local circuitry that resembles the cerebellum. Cerebellum-like structures and the cerebellum itself share common patterns of gene expression and may also share developmental and evolutionary origins. Given these similarities it is natural to ask whether insights gleaned from the study of cerebellum-like structures might be useful for understanding aspects of cerebellar function and vice versa. Work from electrosensory systems has shown that cerebellum-like circuitry acts to generate learned predictions about the sensory consequences of the animals’ own behavior through a process of associative plasticity at parallel fiber synapses. Subtraction of these predictions from the actual sensory input serves to highlight unexpected and hence behaviorally relevant features. Learning and prediction are also central to many current ideas regarding the function of the cerebellum itself. The present review draws comparisons between cerebellum-like structures and the cerebellum focusing on the properties and sites of synaptic plasticity in these structures and on connections between plasticity and learning. Examples are drawn mainly from the electrosensory lobe (ELL) of mormyrid fish and from extensive work characterizing the role of the cerebellum in Pavlovian eyelid conditioning and vestibulo-ocular reflex (VOR) modification. Parallels with other cerebellum-like structures, including the gymnotid ELL, the elasmobranch dorsal octavolateral nucleus (DON), and the mammalian dorsal cochlear nucleus (DCN) are also discussed.

Determinants of pattern recognition by cerebellar Purkinje cells

Many theories of cerebellar function assume that longterm depression (LTD) of parallel fiber (PF) synapses enables Purkinje cells (PCs) to learn to recognize PF activity patterns. According to the classic view, a PC can store and learn to distinguish PF activity patterns that have been presented repeatedly together with climbing fibre (CF) input to the cell. The resulting LTD of the PF synapses is often assumed to lead to a decreased rate of PC simple spike firing, a reduction in the inhibition of their target neurons in the deep cerebellar nuclei and thus an increased output from the cerebellum. We have recently shown by combining computer simulations with electrophysiological recordings in slices and in awake behaving mice that the readout of learned patterns in PCs may operate in a fundamentally different way. Our simulations and experiments predict that the best criterion to distinguish between learned and novel patterns is the duration of a pause in firing that occurs after presentation of a pattern, with shorter pauses in response to learned patterns [1].

Dendritic spike induction of postsynaptic cerebellar LTP

AbstractThe architecture of parallel fiber (PF) axons contacting cerebellar Purkinje neurons (PNs) retains spatial information over long distances. PF synapses can trigger local dendritic calcium spikes, but whether and how this calcium signal leads to plastic changes that decode the PF input organization is unknown. By combining voltage and calcium imaging, we show that PF-elicited calcium signals, mediated by voltage-gated calcium channels, increase non-linearly during high-frequency bursts of electrically constant calcium spikes because they locally and transiently saturate the endogenous buffer. We demonstrate that these non-linear calcium signals, independently of NMDA or metabotropic glutamate receptor activation, can induce PF long-term potentiation (LTP). Two-photon imaging in coronal slices revealed that calcium signals inducing LTP can be observed by stimulating either the PF or the ascending fiber pathway. We propose that local dendritic calcium spikes, evoked by synaptic potentials, provide a unique mechanism to spatially decode PF signals into cerebellar circuitry changes.