Parallel Fiber Inputs Research Articles

Altered Cerebellar Circuitry following Thoracic Spinal Cord Injury in Adult Rats.

Cerebellar function is critical for coordinating movement and motor learning. However, events occurring in the cerebellum following spinal cord injury (SCI) have not been investigated in detail. We provide evidence of SCI-induced cerebellar synaptic changes involving a loss of granule cell parallel fiber input to distal regions of the Purkinje cell dendritic tree. This is accompanied by an apparent increase in synaptic contacts to Purkinje cell proximal dendrites, presumably from climbing fibers originating in the inferior olive. We also observed an early stage injury-induced decrease in the levels of cerebellin-1, a synaptic organizing molecule that is critical for establishing and maintaining parallel fiber-Purkinje cell synaptic integrity. Interestingly, this transsynaptic reorganizational pattern is consistent with that reported during development and in certain transgenic mouse models. To our knowledge, such a reorganizational event has not been described in response to SCI in adult rats. Regardless, the novel results of this study are important for understanding SCI-induced synaptic changes in the cerebellum, which may prove critical for strategies focusing on promoting functional recovery.

Purkinje cells: the forest shapes the trees

Purkinje cells are at the heart of all theories about the olivo-cerbellar circuit as they provide the only output from the cerebellar cortex. Hallmark is their planar morphology in a plane perpendicular to the parallel fibers. Moreover, individual Purkinje cells have very dense dendritic arborizations, a feature commonly referred to as space-filling. In a population, they neatly align and cover the available volume in both transverse and medio-lateral directions, so-called tiling. These remarkable morphological features are assumed to allow neurons to intercept as many parallel fibers inputs as possible; up to 250.000 in individual cells. But it remains an open question how individual cells develop a mono-planar dendrite and how the alignment emerges in a population. Here we address both questions. We recently developed a computational framework, NeuroMaC, to investigate how neuronal morphologies are shaped by interactions with the environment in which they are embedded [1]. In this approach, large numbers of virtual morphologies are generated simultaneously by repeatedly extending simulated growth-cones that follow growth rules expressed in terms of environmental interactions. In this work, we hypothesized that the peculiar Purkinje cell morphology emerges from three simple interactions with its environment. First, dendritic branches of one neuron are repelled by each other, a process called self-avoidance. Second, dendritic branches of different neurons repel each other. Third, all branches are to some extent attracted to the pia surface. Initial simulated growth-cones where placed on a seven-by-seven lattice with plausible spacing: somata where 25 and 150 micron apart from each other in, respectively, the medio-lateral and transverse directions. We found that these simple rules yielded highly realistic morphologies exhibiting the hallmark planarity in the transverse direction. The planarity emerged because the repulsion between branches forced the neuron to occupy all available space, which was larger in the transverse than in the medio-lateral direction. We validated the resulting morphologies against exemplar data and found a good statistical match. Moreover, alignment and tiling emerged in the population. We demonstrated that key features of the notoriously complex Purkinje cell morphology could be achieved by solely local repulsive and attractive interactions between simulated growth-cones. Thus, we may conclude that the forest does shape individual neurons. While alignment did emerge to a certain extent, it is hard to validate because there is currently no data available on Purkinje cell forests. We also speculate on the necessity of a global organization mechanism that consistently aligns Purkinje cells in the transverse direction.

The ionic mechanism of the Purkinje cell dendritic spikes generation and propagation: a model exploration

Due to the lack of sodium channel expression in the Purkinje cell (PC) dendrite, the passively propagated sodium spikes can hardly be detected in the dendrite. However, the substantial expression of T type calcium channels (ICaT) and P type calcium channels (ICaP) can cause local regenerative spikes to occur in the dendrite after receiving a parallel fiber (PF) stimulus [1]. In this study, with the previously published PC dendrite model [2] from our group as the starting point, we have built a new PC dendrite model incorporating the low threshold A-type K+ current (IKA) [3], high threshold activated K+ current (IKV3) and hyperpolarization-activated cation current (Ih). In our model, in agreement with experimental observations [1], the EPSP amplitude increases nonlinearly with the strength of the PF synaptic input until it reaches the spike threshold. During this range, we find that ICaT amplifies the EPSP caused by PF synaptic input to boost the EPSP close to the spike threshold. Around the spike threshold there is an obvious spike delay due to the interactive role of IKA and ICaT. Above the spike threshold, high threshold activated ICaP takes over and depolarizes the dendrite rapidly, finally leading to the generation of dendritic spikes. The amplitude of dendritic spikes doesn't increase further with the stimulation intensity and is mainly determined by the struggle among ICaP, IKV3 and high conductance calcium activated K+ currents (IBK). Injecting a negative current can eliminate the PF input evoked dendritic spikes by lowering the membrane potential which implies less activation of the ICaT and subsequent less amplification of the EPSP. We also find that the simulated dendritic spikes can't propagate to the whole dendrite due to the regulating role of mainly IBK and IKV3. Surprisingly by partially blocking IKV3 and IBK parallel fiber evoked dendritic spikes can propagate to the whole dendrite because of the broadening of its width. The calcium influx by dendritic spikes is vital to a lot of calcium dependent processes like synaptic plasticity. Understanding the mechanism of generation of the local dendritic spikes evoked by PF stimulus and how their localized nature works will help us better explore how information is processed in the PC dendrite.

Oxygen–glucose deprivation increases firing of unipolar brush cells and enhances spontaneous EPSCs in Purkinje cells in the vestibulo-cerebellum

Unipolar brush cells (UBCs) are excitatory interneurons in the granular layer of the cerebellar cortex, which are predominantly distributed in the vestibulo-cerebellar region. The unique firing properties and synaptic connections of UBCs may underlie lobular heterogeneity of excitability in the granular layer and the susceptibility to ischemia-induced excitotoxicity. In this study, we investigated the effects of oxygen–glucose deprivation (OGD) on the firing properties of UBCs and granule cells and spontaneous excitatory postsynaptic currents (sEPSCs) of Purkinje cells using whole-cell recordings. Short-term OGD induced increases in spontaneous firing of UBCs by causing membrane depolarization via the activation of NMDA receptors. UBC firing indirectly affected Purkinje cells by altering parallel fiber inputs of a subset granule cells, resulting in a marked increase in sEPSCs in Purkinje cells in vestibulo-cerebellar lobules IX–X, but not in lobules IV–VI, which have fewer UBCs. Similarly, the frequency and amplitude of sEPSCs in Purkinje cells were significantly greater in lobules IX–X than in IV–VI, even in control conditions. These results reveal that UBCs play key roles in regulating local excitability in the granular layer, resulting in lobular heterogeneity in the susceptibility to ischemic insult in the cerebellum.

Reading out a spatiotemporal population code by imaging neighbouring parallel fibre axons in vivo

The spatiotemporal pattern of synaptic inputs to the dendritic tree is crucial for synaptic integration and plasticity. However, it is not known if input patterns driven by sensory stimuli are structured or random. Here we investigate the spatial patterning of synaptic inputs by directly monitoring presynaptic activity in the intact mouse brain on the micron scale. Using in vivo calcium imaging of multiple neighbouring cerebellar parallel fibre axons, we find evidence for clustered patterns of axonal activity during sensory processing. The clustered parallel fibre input we observe is ideally suited for driving dendritic spikes, postsynaptic calcium signalling, and synaptic plasticity in downstream Purkinje cells, and is thus likely to be a major feature of cerebellar function during sensory processing.

Integration of Purkinje cell inhibition by cerebellar nucleo-olivary neurons.

Neurons in the cerebellar cortex, cerebellar nuclei, and inferior olive (IO) form a trisynaptic loop critical for motor learning. IO neurons excite Purkinje cells via climbing fibers and depress their parallel fiber inputs. Purkinje cells inhibit diverse cells in the cerebellar nuclei, including small GABAergic nucleo-olivary neurons that project to the IO. To investigate how these neurons integrate synaptic signals from Purkinje cells, we retrogradely labeled nucleo-olivary cells in the contralateral interpositus and lateral nuclei with cholera toxin subunit B-Alexa Fluor 488 and recorded their electrophysiological properties in cerebellar slices from weanling mice. Nucleo-olivary cells fired action potentials over a relatively narrow dynamic range (maximal rate, ∼ 70 spikes/s), unlike large cells that project to premotor areas (maximal rate, ∼ 400 spikes/s). GABA(A) receptor-mediated IPSCs evoked by electrical or optogenetic stimulation of Purkinje cells were more than 10-fold slower in nucleo-olivary cells (decay time, ∼ 25 ms) than in large cells (∼ 2 ms), and repetitive stimulation at 20-150 Hz evoked greatly summating IPSCs. Nucleo-olivary firing rates varied inversely with IPSP frequency, and the timing of Purkinje IPSPs and nucleo-olivary spikes was uncorrelated. These attributes contrast with large cells, whose brief IPSCs and rapid firing rates can permit well timed postinhibitory spiking. Thus, the intrinsic and synaptic properties of these two projection neurons from the cerebellar nuclei tailor them for differential integration and transmission of their Purkinje cell input.

Localization of Presynaptic Plasticity Mechanisms Enables Functional Independence of Synaptic and Ectopic Transmission in the Cerebellum.

In the cerebellar molecular layer parallel fibre terminals release glutamate from both the active zone and from extrasynaptic “ectopic” sites. Ectopic release mediates transmission to the Bergmann glia that ensheathe the synapse, activating Ca2+-permeable AMPA receptors and glutamate transporters. Parallel fibre terminals exhibit several forms of presynaptic plasticity, including cAMP-dependent long-term potentiation and endocannabinoid-dependent long-term depression, but it is not known whether these presynaptic forms of long-term plasticity also influence ectopic transmission to Bergmann glia. Stimulation of parallel fibre inputs at 16 Hz evoked LTP of synaptic transmission, but LTD of ectopic transmission. Pharmacological activation of adenylyl cyclase by forskolin caused LTP at Purkinje neurons, but only transient potentiation at Bergmann glia, reinforcing the concept that ectopic sites lack the capacity to express sustained cAMP-dependent potentiation. Activation of mGluR1 caused depression of synaptic transmission via retrograde endocannabinoid signalling but had no significant effect at ectopic sites. In contrast, activation of NMDA receptors suppressed both synaptic and ectopic transmission. The results suggest that the signalling mechanisms for presynaptic LTP and retrograde depression by endocannabinoids are restricted to the active zone at parallel fibre synapses, allowing independent modulation of synaptic transmission to Purkinje neurons and ectopic transmission to Bergmann glia.

Intracellular calcium dynamics permit a Purkinje neuron model to perform toggle and gain computations upon its inputs.

Without synaptic input, Purkinje neurons can spontaneously fire in a repeating trimodal pattern that consists of tonic spiking, bursting and quiescence. Climbing fiber input (CF) switches Purkinje neurons out of the trimodal firing pattern and toggles them between a tonic firing and a quiescent state, while setting the gain of their response to Parallel Fiber (PF) input. The basis to this transition is unclear. We investigate it using a biophysical Purkinje cell model under conditions of CF and PF input. The model can replicate these toggle and gain functions, dependent upon a novel account of intracellular calcium dynamics that we hypothesize to be applicable in real Purkinje cells.

Ultra-rapid axon-axon ephaptic inhibition of cerebellar Purkinje cells by the pinceau

Excitatory synaptic activity in the brain is shaped and balanced by inhibition. Because inhibition cannot propagate, it is often recruited with a synaptic delay by incoming excitation. Cerebellar Purkinje cells are driven by long-range excitatory parallel fiber inputs, which also recruit local inhibitory basket cells. The axon initial segment of each Purkinje cell is ensheathed by basket cell axons in a structure called the pinceau, which is largely devoid of chemical synapses. In mice, we found at the single-cell level that the pinceau mediates ephaptic inhibition of Purkinje cell firing at the site of spike initiation. The reduction of firing rate was synchronous with the presynaptic action potential, eliminating a synaptic delay and allowing granule cells to inhibit Purkinje cells without a preceding phase of excitation. Axon-axon ephaptic intercellular signaling can therefore mediate near-instantaneous feedforward and lateral inhibition.

Type 1 metabotropic glutamate receptors (m G lu1) trigger the gating of G lu D 2 delta glutamate receptors

The orphan GluD2 receptor belongs to the ionotropic glutamate receptor family but does not bind glutamate. Ligand-gated GluD2 currents have never been evidenced, and whether GluD2 operates as an ion channel has been a long-standing question. Here, we show that GluD2 gating is triggered by type 1 metabotropic glutamate receptors, both in a heterologous expression system and in Purkinje cells. Thus, GluD2 is not only an adhesion molecule at synapses but also works as a channel. This gating mechanism reveals new properties of glutamate receptors that emerge from their interaction and opens unexpected perspectives regarding synaptic transmission and plasticity.

Quantification of the density of cooperative neighboring synapses required to evoke endocannabinoid signaling

The spatial pattern of synapse activation may impact on synaptic plasticity. This applies to the synaptically-evoked endocannabinoid-mediated short-term depression at the parallel fiber (PF) to Purkinje cell synapse, the occurrence of which requires close proximity between the activated synapses. Here, we determine quantitatively this required proximity, helped by the geometrical organization of the cerebellar molecular layer. Transgenic mice expressing a calcium indicator selectively in granule cells enabled the imaging of action potential-evoked presynaptic calcium rise in isolated, single PFs. This measurement was used to derive the number of PFs activated within a beam of PFs stimulated in the molecular layer, from which the density of activated PFs (input density) was calculated. This density was on average 2.8μm−2 in sagittal slices and twice more in transverse slices. The synaptically-evoked endocannabinoid-mediated suppression of excitation (SSE) evoked by ten stimuli at 200Hz was determined from the monitoring of either postsynaptic responses or presynaptic calcium rise. The SSE was significantly larger when recorded in transverse slices, where the input density is larger. The exponential description of the SSE plotted as a function of the input density suggests that the SSE is half reduced when the input density decreases from 6 to 2μm−2. We conclude that, although all PFs are truncated in an acute sagittal slice, half of them remain respondent to stimulation, and activated synapses need to be closer than 1.5μm to synergize in endocannabinoid signaling.

The Long-term Structural Plasticity of Cerebellar Parallel Fiber Axons and Its Modulation by Motor Learning

Presynaptic axonal varicosities, like postsynaptic spines, are dynamically added and eliminated even in mature neuronal circuitry. To study the role of this axonal structural plasticity in behavioral learning, we performed two-photon in vivo imaging of cerebellar parallel fibers (PFs) in adult mice. PFs make excitatory synapses on Purkinje cells (PCs) in the cerebellar cortex, and long-term potentiation and depression at PF-PC synapses are thought to play crucial roles in cerebellar-dependent learning. Time-lapse vital imaging of PFs revealed that, under a control condition (no behavioral training), ∼10% of PF varicosities appeared and disappeared over a period of 2 weeks without changing the total number of varicosities. The fraction of dynamic PF varicosities significantly diminished during training on an acrobatic motor skill learning task, largely because of reduced addition of new varicosities. Thus, this form of motor learning was associated with greater structural stability of PFs and a slight decrease in the total number of varicosities. Together with prior findings that the number of PF-PC synapses increases during similar training, our results suggest that acrobatic motor skill learning involves a reduction of some PF inputs and a strengthening of others, probably via the conversion of some preexisting PF varicosities into multisynaptic terminals.

Parallel fiber and climbing fiber responses in rat cerebellar cortical neurons in vivo

Over the last few years we have seen a rapidly increasing interest in the functions of the inhibitory interneurons of the cerebellar cortex. However, we still have very limited knowledge about their physiological properties in vivo. The present study provides the first description of their spontaneous firing properties and their responses to synaptic inputs under non-anesthetized conditions in the decerebrated rat in vivo. We describe the spike responses of molecular layer interneurons (MLI) in the hemispheric crus1/crus2 region and compare them with those of Purkinje cells (PCs) and Golgi cells (GCs), both with respect to spontaneous activity and responses evoked by direct electrical stimulation of parallel fibers (PFs) and climbing fibers (CFs). In agreement with previous findings in the cat, we found that the CF responses in the interneurons consisted of relatively long lasting excitatory modulations of the spike firing. In contrast, activation of PFs induced rapid but short-lasting excitatory spike responses in all types of neurons. We also explored PF input plasticity in the short-term (10 min) using combinations of PF and CF stimulation. With regard to in vivo recordings from cerebellar cortical neurons in the rat, the data presented here provide the first demonstration that PF input to PC can be potentiated using PF burst stimulation and they suggest that PF burst stimulation combined with CF input may lead to potentiation of PF inputs in MLIs. We conclude that the basic responsive properties of the cerebellar cortical neurons in the rat in vivo are similar to those observed in the cat and also that it is likely that similar mechanisms of PF input plasticity apply.

Opsoclonus: Clinical and immunological features

BackgroundOpsoclonus is felt to be a saccadic oscillation disorder but the neuroanatomical substrate for generating the abnormal eye movements is poorly understood. MethodsWe recorded eye movements and studied serum samples from 7 patients who presented with opsoclonus and with either myoclonus or generalized tremor. Anti neuronal antibodies were detected by immunohistochemestry using rat and human cerebellar sections. ResultsIn all patients but one the opsoclonus resolved within 2weeks (after immunosuppression in 4, resection of the underlying neoplasm in 1 and spontaneously in 1). Opsoclonus was arrhythmic and multidirectional with a wide frequency range (4–10Hz). No known paraneoplastic antibodies were found in the initial commercial screen. Three patients had antiPurkinje cell antibodies with a characteristic punctate staining in the molecular layer. ConclusionsThe clinical and immunological findings are consistent with the hypothesis, that in some patients, opsoclonus results from antibodies directed at the parallel fiber-Purkinje cell synapse. The antibodies block parallel fiber input to Purkinje cells allowing spontaneous oscillating activity generated in the inferior olives to be passed on to the oculomotor nuclei via the flocculus.

Cav3-KCa3.1 complex enhances detection of facilitating parallel fiber inputs in cerebellar Purkinje cells

The ability for a neuron to distinguish important input signals from background noise is essential for proper circuit function. Several mechanisms exist to enhance signal detection. For example, short-term facilitation enhances burst transmission, while information from single spikes is transmitted more effectively through synapses that exhibit depression [1]. However, in the case of cerebellar Purkinje cells, where thousands of parallel fiber (PF) synaptic inputs impinge on the dendritic tree, postsynaptic mechanisms must play a role in increasing signal-to-noise ratio. Specifically, mechanisms must exist in Purkinje cells that allow transmission of granule cell bursts carrying sensory information while filtering out background input. Recently, we demonstrated that low voltage activated Cav3 calcium channels form a complex with intermediate conductance calcium-activated potassium channels (KCa3.1) in Purkinje cells [2]. We proposed that the Cav3-KCa3.1 complex enhances signal detection capabilities by selectively suppressing non-facilitating background inputs while allowing facilitating parallel fiber inputs to generate Purkinje cell spike output. We used a combination of modeling and experimental methods to examine the role of the Cav3-KCa3.1 complex in simultaneously enhancing detection of parallel fiber bursts and suppressing background inputs. The Cav3-KCa3.1 complex was simulated using a calcium-diffusion model with 10 hemispherical compartments around the Cav3 channel and the KCa3.1 channel placed within 50 nm of the calcium source. The Cav3-KCa3.1 complex was included in a single-compartment membrane model with HCN and synaptic conductances to determine its effect on excitatory postsynaptic potential (EPSP) summation. Whole-cell current-clamp recordings of Purkinje cells were also made from acute slices of rat cerebellum (P18-P25). Parallel fibers were stimulated using a monopolar stimulating electrode in the cerebellar molecular layer. We simulated 5 pulse 50 Hz trains of facilitating and non-facilitating EPSPs in the model. The Cav3-KCa3.1 complex reduced the summation of both sets of inputs. However, the facilitating inputs achieved a higher degree of summation than non-facilitating inputs, even though charge transfer for both trains was identical. Examination of the KCa3.1 current showed that synaptic facilitation compensated for the increase in KCa3.1 activation during the input train, allowing EPSPs to summate to higher voltages. When the Cav3-KCa3.1 complex was not included in the model, facilitating and non-facilitating inputs reached similar degrees of summation. Our computational results were confirmed by our current clamp recordings. Facilitating inputs evoked by direct PF stimulation generated more depolarization and spikes in Purkinje cells than non-facilitating simulated EPSPs (simEPSPs). During trains of simEPSPs, a supralinear increase in the rate of EPSP decay was observed for consecutive inputs, indicating an increased recruitment of hyperpolarizing current during the train. Application of Ni2+ (100 μM) to block Cav3 current removed this supralinear increase in rate of decay, confirming that the Cav3-KCa3.1 complex dynamically changes temporal summation during repetitive input trains. Our results demonstrate that the Cav3-KCa3.1 complex significantly affects the temporal summation of synaptic inputs. Specifically, the Cav3-KCa3.1 complex allows facilitating inputs from single PF sources to summate and generate spike output in Purkinje cells, while background inputs are quickly suppressed, improving the ability to respond to important sensory information.

Control of a manipulator kinematics robotic arm on fuzzy cerebellar model articulation controller

While in this paper, we present a model of fuzzy cerebellar cortex that puts together two sorts of learning: feedforward and predictive association founded on learning between granule cell ascending branch and parallel fiber inputs, and reinforcement learning with feedback error correction based on climbing fiber activity. To show the model's utility, we simulated the control of a robotic arm. Specification of the model is successfully used to learn how to control the timing release of the robotic arm in the course of the task. Biological control systems have always been studied as workable inspiration for construction of robotic controllers. The cerebellum can be involved in the production and learning of smooth, coordinated movements. The cerebellum is assumed to be the location of movement coordination within the body. It really is hypothesized that through the use of some form of learned internal model, the cerebellum is able to overcome inherent sensory latency and coordinate fast, accurate movement without needing complex mathematical algorithm. Key words: Cerebellum, predictive, feedforward, cerebellar learning, motor control, CMAC neural network, kinematics.

Intermediate conductance calcium-activated potassium channels modulate summation of parallel fiber input in cerebellar Purkinje cells

Encoding sensory input requires the expression of postsynaptic ion channels to transform key features of afferent input to an appropriate pattern of spike output. Although Ca(2+)-activated K(+) channels are known to control spike frequency in central neurons, Ca(2+)-activated K(+) channels of intermediate conductance (KCa3.1) are believed to be restricted to peripheral neurons. We now report that cerebellar Purkinje cells express KCa3.1 channels, as evidenced through single-cell RT-PCR, immunocytochemistry, pharmacology, and single-channel recordings. Furthermore, KCa3.1 channels coimmunoprecipitate and interact with low voltage-activated Cav3.2 Ca(2+) channels at the nanodomain level to support a previously undescribed transient voltage- and Ca(2+)-dependent current. As a result, subthreshold parallel fiber excitatory postsynaptic potentials (EPSPs) activate Cav3 Ca(2+) influx to trigger a KCa3.1-mediated regulation of the EPSP and subsequent after-hyperpolarization. The Cav3-KCa3.1 complex provides powerful control over temporal summation of EPSPs, effectively suppressing low frequencies of parallel fiber input. KCa3.1 channels thus contribute to a high-pass filter that allows Purkinje cells to respond preferentially to high-frequency parallel fiber bursts characteristic of sensory input.

Parasagittal Zones in the Cerebellar Cortex Differ in Excitability, Information Processing, and Synaptic Plasticity

At the molecular and circuitry levels, the cerebellum exhibits a striking parasagittal zonation as exemplified by the spatial distribution of molecules expressed on Purkinje cells and the topography of the afferent and efferent projections. The physiology and function of the zonation is less clear. Activity-dependent optical imaging has proven a useful tool to examine the physiological properties of the parasagittal zonation in the intact animal. Recent findings show that zebrin II-positive and zebrin II-negative zones differ markedly in their responses to parallel fiber inputs. These findings suggest that cerebellar cortical excitability, information processing, and synaptic plasticity depend on the intrinsic properties of different parasagittal zones.

How do climbing fibers teach?

How do climbing fibers teach?

Sustained Firing of Cartwheel Cells in the Dorsal Cochlear Nucleus Evokes Endocannabinoid Release and Retrograde Suppression of Parallel Fiber Synapses

Neurons in many brain regions release endocannabinoids from their dendrites that act as retrograde signals to transiently suppress neurotransmitter release from presynaptic terminals. Little is known, however, about the physiological mechanisms of short-term endocannabinoid-mediated plasticity under physiological conditions. Here we investigate calcium-dependent endocannabinoid release from cartwheel cells (CWCs) of the mouse dorsal cochlear nucleus (DCN) in the auditory brainstem that provide feedforward inhibition onto DCN principal neurons. We report that sustained action potential firing by CWCs evokes endocannabinoid release in response to submicromolar elevation of dendritic calcium that transiently suppresses their parallel fiber (PF) inputs by >70%. Basal spontaneous CWC firing rates are insufficient to evoke tonic suppression of PF synapses. However, elevating CWC firing rates by stimulating PFs triggers the release of endocannabinoids and heterosynaptic suppression of PF inputs. Spike-evoked suppression by endocannabinoids selectively suppresses excitatory synapses, but glycinergic/GABAergic inputs onto CWCs are not affected. Our findings demonstrate a mechanism of transient plasticity mediated by endocannabinoids that heterosynaptically suppresses subsets of excitatory presynaptic inputs to CWCs that regulates feedforward inhibition of DCN principal neurons and may influence the output of the DCN.