Modulatory effects of parallel fiber and molecular layer interneuron synaptic activity on purkinje cell responses to ascending segment input: a modeling study

Based on anatomical, physiological, and model-based studies, it has been proposed that synapses associated with the ascending segment of granule cell axons provide the principle excitatory drive on Purkinje cells which is then modulated by the more numerous parallel fiber synapses. In this study we have evaluated this idea using a detailed compartmental model of a cerebellar Purkinje cell by providing identical ascending segment synaptic inputs during different levels of random parallel fiber and molecular interneuron input. Results suggest that background inputs from parallel fibers and molecular layer interneurons can have a substantial effect on the response of Purkinje cells to ascending segment inputs. Interestingly, these effects are not reflected in the average firing rate of the Purkinje cell and are thus entirely dendritic in effect. These results are considered in the context of the known segregated spatial distribution of the parallel fibers and ascending segment synapses and a new hypothesis concerning the functional organization of cerebellar cortical circuitry.     

Neural expectation: cerebellar and retinal analogs of cells fired by learnable or unlearned pattern classes

Neural networks are introduced which can be taught by classical or instrumental conditioning to fire in response to arbitrary learned classes of patterns. The filters of output cells are biased by presetting cells whose activation prepares the output cell to expect prescribed patterns. For example, an animal that learns to expect food in response to a lever press becomes frustrated if food does not follow the lever press. It's expectations are thereby modified, since frustration is negatively reinforcing. A neural analog with aspects of cerebellar circuitry is noted, including diffuse mossy fiber inputs feeding parallel fibers that end in Purkinje cell dendrites, climbing fiber inputs ending in Purkinje cell dendrites and giving off collaterals to nuclear cells, and inhibitory Purkinje cell outputs to nuclear cells. The networks are motivated by studying mechanisms of pattern discrimination that require no learning. The latter often use two successive layers of inhibition, analogous to horizontal and amacrine cell layers in vertebrate retinas. Cells exhibiting hue (in)constancy, brightness (in)constancy, or movement detection properties are included. These results are relevant to Land's retinex theory and to the existence of opponent- and nonopponent-type cell responses in retinal cells. Some adaptation mechanisms, and arousal mechanisms for crispening the pattern weights that can fire a given cell, are noted.Supported in part by the Alfred P. Sloan Foundation and the Office of Naval Research (N00014-67-A-0204-0051).     

Cerebellar globular cells receive monoaminergic excitation and monosynaptic inhibition from Purkinje cells

Inhibitory interneurons in the cerebellar granular layer are more heterogeneous than traditionally depicted. In contrast to Golgi cells, which are ubiquitously distributed in the granular layer, small fusiform Lugaro cells and globular cells are located underneath the Purkinje cell layer and small in number. Globular cells have not been characterized physiologically. Here, using cerebellar slices obtained from a strain of gene-manipulated mice expressing GFP specifically in GABAergic neurons, we morphologically identified globular cells, and compared their synaptic activity and monoaminergic influence of their electrical activity with those of small Golgi cells and small fusiform Lugaro cells. Globular cells were characterized by prominent IPSCs together with monosynaptic inputs from the axon collaterals of Purkinje cells, whereas small Golgi cells or small fusiform Lugaro cells displayed fewer and smaller spontaneous IPSCs. Globular cells were silent at rest and fired spike discharges in response to application of either serotonin (5-HT) or noradrenaline. The two monoamines also facilitated small Golgi cell firing, but only 5-HT elicited firing in small fusiform Lugaro cells. Furthermore, globular cells likely received excitatory monosynaptic inputs through mossy fibers. Because globular cells project their axons long in the transversal direction, the neuronal circuit that includes interplay between Purkinje cells and globular cells could regulate Purkinje cell activity in different microzones under the influence of monoamines and mossy fiber inputs, suggesting that globular cells likely play a unique modulatory role in cerebellar motor control.     

Potentiation of mossy fiber EPSCs in the cerebellar nuclei by NMDA receptor activation followed by postinhibitory rebound current

Behavioral and computational studies predict that synaptic plasticity of excitatory mossy fiber inputs to cerebellar nuclear neurons is required for associative learning, but standard tetanization protocols fail to potentiate nuclear cell EPSCs in mouse cerebellar slices. Nuclear neurons fire action potentials spontaneously unless strongly inhibited by Purkinje neurons, raising the possibility that plasticity-triggering signals in these cells differ from those at classical Hebbian synapses. Based on predictions of neuronal activity during delay eyelid conditioning, we developed quasi-physiological induction protocols consisting of high-frequency mossy fiber stimulation and postsynaptic hyperpolarization. Robust, NMDA receptor-dependent potentiation of nuclear cell EPSCs occurred with protocols including a 150-250 ms hyperpolarization in which mossy fiber stimulation preceded a postinhibitory rebound depolarization. Mossy fiber stimulation potentiated EPSCs even when postsynaptic spiking was prevented by voltage-clamp, as long as rebound current was evoked. These data suggest that Purkinje cell inhibition guides the strengthening of excitatory synapses in the cerebellar nuclei.     

Lateral dendritic shunt inhibition can regularize mitral cell spike patterning

Mitral cells, the principal output neurons of the olfactory bulb, receive direct synaptic activation from primary sensory neurons. Shunting inhibitory inputs delivered by granule cell interneurons onto mitral cell lateral dendrites, while poorly positioned to prevent spike initiation, are believed to influence spike timing and underlie coordinated field potential oscillations. We investigated this phenomenon in a reduced compartmental mitral cell model suitable for incorporation into network simulations. Lateral dendritic shunt conductances delayed spiking to a degree dependent on both their electrotonic distance and phase of onset. Moreover, when the afferent activation of mitral cells was loosely coordinated in time, recurrent inhibition significantly narrowed the distribution of mitral cell spike times, illustrating a tendency towards coordinated synchronous activity. However, if mitral cell activity was initially disorganized, recurrent inhibition actually increased the variance in spike timing. This result suggests an essential role for early mechanisms of temporal coordination in olfaction, such as sniffing and the initial synchronization of mitral cell intrinsic oscillations by periglomerular cell-mediated inhibition.     

Interactions between cerebellar Purkinje cells and their associated astrocytes

Some neurons, including cerebellar Purkinje cells, are completely ensheathed by astrocytes. When granule cell neurons and functional glia were eliminated from newborn mouse cerebellar cultures by initial exposure to a DNA synthesis inhibitor, Purkinje cells lacked glial sheaths and there was a tremendous sprouting of Purkinje cell recurrent axon collaterals, terminals of which hyperinnervated Purkinje cell somata, including persistent somatic spines, and formed heterotypical synapses with Purkinje cell dendritic spines, sites usually occupied by parallel fiber (granule cell axon) terminals. Purkinje cells in such preparations failed to develop complex spikes when recorded from intracellularly, and their membrane input resistances were low, making them less sensitive to inhibitory input. If granule cells and oligodendrocytes were eliminated, but astrocytes were not compromised, sprouting of recurrent axon collaterals occurred and their terminals projected to Purkinje cell dendritic spines, but the Purkinje cells had astrocytic sheaths, their somata were not hyperinnervated, the somatic spines had disappeared, complex spike discharges predominated, and membrane input resistance was like that of Purkinje cells in untreated control cultures. When cerebellar cultures without granule cells and glia were transplanted with granule cells and/or glia from another source, a series of changes occurred that included stripping of excess Purkinje cell axosomatic synapses by astrocytic processes, reduction of heterotypical axospinous synapses in the presence of astrocytes, disappearance of Purkinje cell somatic spines with astrocytic ensheathment, and proliferation of Purkinje cell dendritic spines after the introduction of astrocytes. Dendritic spine proliferation was followed by formation of homotypical axospinous synapses when granule cells were present or persistence as unattached spines in the absence of granule cells. The results of these studies indicate that astrocytes regulate the numbers of Purkinje cell axosomatic and axospinous synapses, induce Purkinje cell dendritic spine proliferation, and promote the structural and functional maturation of Purkinje cells.     

Expression of zebrafish glutamate receptor delta2 in neurons with cerebellum-like wiring

Mammalian glutamate receptor (GluR) delta2 is selectively expressed in cerebellar Purkinje cells and plays key roles in cerebellar plasticity, motor learning, and neural wiring. Here, we isolated cDNA encoding the zebrafish ortholog of mammalian GluRdelta2. We found that in adult zebrafish brain, glurdelta2 mRNA was expressed not only in cerebellar Purkinje cells, but also in the crest cells of the medial octavolateral nucleus (MON) and the type I neurons of the optic tectum. Immunohistochemical analysis revealed that zebrafish GluRdelta2 proteins were selectively localized in the apical dendrites of these neurons. Interestingly, the crest cells of the MON and the type I neurons of the optic tectum receive large numbers of parallel fiber inputs at the apical dendrites and sensory inputs at the proximal or basal dendrites. These results suggest that the expression of zebrafish GluRdelta2 is selective for cerebellum-like neural wiring with large numbers of parallel fiber inputs.     

Light and scanning electron microscopic study of cerebellar cortex of teleost fishes

Summary The teleostean cerebellar cortex has been studied with respect to its cytoarchitectonic arrangement and intracortical neuronal circuits. Samples of fish cerebellum were fixed either by immersion or vascular perfusion in 5% glutaraldehyde solution and processed for light and scanning electron microscopy. The cerebellar cortex shows four distinct layers: granular; fibrous stratum; Purkinje cell; and molecular layers. In the granular layer, mossy and climbing fiber glomeruli were characterized. The mossy glomerular region appeared as polygonal, round or ovoid clews formed by the convergence of up to 17 dendritic profiles upon a thick mossy fiber branch. The en passant nature of mossy fiber-granule cell dendrite synaptic relationship was clearly appreciated. The climbing fibers showed tendril and glomerular collaterals. The latter form thin, elongated glomeruli. Remnants of a neuroglial envelope were observed in the mossy fiber glomeruli but are apparently absent from the climbing fiber glomeruli. The beaded-shape Golgi cell axonal ramifications were observed participating in the formation of both glomerular types. Velate protoplasmic astrocytes and oligodendrocytes were also identified. The fibrous stratum appeared to be formed by compact bundles of thick and thin myelinated axons, running horizontally beneath the Purkinje cell layer and apparently belonging to ascending climbing fibers and descending Purkinje cell axons. At the Purkinje cell layer a selective removal of Bergmann glial cells was observed allowing the visualization of the pericellular basket and the pinceaux. Climbing fiber stems and their tendril collaterals were seen on their way to the molecular layer ascending parallel to the Purkinje dendritic ramifications. Stellate neuron processes were found passing through the fan-like arborescence of Purkinje cell dendrites.     

The effect of SK channel modulators on the simple spike firing frequency in discharge of cerebellar Purkinje cells in laboratory mice

The activity of cerebellar Purkinje cells is studied as affected by CyPPA, a positive modulator of small-conductance calcium-activated potassium channels type 3 and 2 (SK3/SK2), and NS309, an activator of small- and intermediate-conductance calcium-activated potassium channels (IK/SK), in male two-month-old laboratory mice. CyPPA decreases the simple spike firing frequency in the discharge of Purkinje cells by an average of 25% 1 hour after application of 1mM of the compound. An application of 100 μM of NS309 reduces the simple spike firing frequency by an average of 47% during the same period. These results confirm the hypothesis that SK channels may be involved in the downregulation of simple spike firing frequency in Purkinje cells. The frequency-regulating effect of NS309 is stronger, suggesting that IK/SK channels play a decisive role in the regulation of Purkinje cell spiking activity. Since an increase of simple spike firing frequency in these cells is symptomatic of many locomotor activity disorders, e.g., spinocerebellar ataxia, the substances studied or their functional analogues might be of medicinal interest.     

Signal processing in cerebellar Purkinje cells

Mechanisms and functional implications of signal processing in cerebellar Purkinje cells have been the subject of recent extensive investigations. Complex patterns of their planar dendritic arbor are analysed with computer-aided reconstructions and also topological analyses. Local computation may occur in Purkinje cell dendrites, but its extent is not clear at present. Synaptic transmission and electrical and ionic activity of Purkinje cell membrane have been revealed in detail, and related biochemical processes are being uncovered. A special type of synaptic plasticity is present in Purkinje cell dendrites; long-term depression (LTD) occurs in parallel fiber-Purkinje cell transmission when the parallel fibers are activated with a climbing fiber innervating that Purkinje cell. Evidence indicates that synaptic plasticity in Purkinje cells is due to sustained desensitization of Purkinje dendritic receptors to glutamate, which is a putative neurotransmitter of parallel fibers, and that conjunctive activation of a climbing fiber and parallel fibers leads to desensitization through enhanced intradendritic calcium concentration. A microzone of the cerebellar cortex is connected to an extracerebellar neural system through the inhibitory projection of Purkinje cells to a cerebellar or vestibular nuclear cell group. Climbing fiber afferents convey signals representing control errors in the performance of a neural system, and evoke complex spikes in Purkinje cells of the microzone connected to the neural system. Complex spikes would modify the performance of the microzone by producing LTD in parallel fiber-Purkinje cell synapses, and consequently would improve the overall performance of the neural system. The primary function of the cerebellum thus appears to be endowing adaptability to numerous neural control systems in the brain and spinal cord through error-triggered reorganization of the cerebellar cortical circuitry.     

Synaptic responses evoked by tactile stimuli in Purkinje cells in mouse cerebellar cortex Crus II in vivo

Background

Sensory stimuli evoke responses in cerebellar Purkinje cells (PCs) via the mossy fiber-granule cell pathway. However, the properties of synaptic responses evoked by tactile stimulation in cerebellar PCs are unknown. The present study investigated the synaptic responses of PCs in response to an air-puff stimulation on the ipsilateral whisker pad in urethane-anesthetized mice.

Methods and Main Results

Thirty-three PCs were recorded from 48 urethane-anesthetized adult (6–8-week-old) HA/ICR mice by somatic or dendritic patch-clamp recording and pharmacological methods. Tactile stimulation to the ipsilateral whisker pad was delivered by an air-puff through a 12-gauge stainless steel tube connected with a pressurized injection system. Under current-clamp conditions (I = 0), the air-puff stimulation evoked strong inhibitory postsynaptic potentials (IPSPs) in the somata of PCs. Application of SR95531, a specific GABA_A receptor antagonist, blocked IPSPs and revealed stimulation-evoked simple spike firing. Under voltage-clamp conditions, tactile stimulation evoked a sequence of transient inward currents followed by strong outward currents in the somata and dendrites in PCs. Application of SR95531 blocked outward currents and revealed excitatory postsynaptic currents (EPSCs) in somata and a temporal summation of parallel fiber EPSCs in PC dendrites. We also demonstrated that PCs respond to both the onset and offset of the air-puff stimulation.

Conclusions

These findings indicated that tactile stimulation induced asynchronous parallel fiber excitatory inputs onto the dendrites of PCs, and failed to evoke strong EPSCs and spike firing in PCs, but induced the rapid activation of strong GABA_A receptor-mediated inhibitory postsynaptic currents in the somata and dendrites of PCs in the cerebellar cortex Crus II in urethane-anesthetized mice.     

δ-Glutamate Receptors Are Differentially Distributed at Parallel and Climbing Fiber Synapses on Purkinje Cells

Abstract: Neurons containing multiple excitatory inputs may sort and target glutamate receptor subtypes to subsets of synapses. A good model for testing this hypothesis is the Purkinje cell, which expresses significant levels of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate, kainate, N -methyl- d -aspartate, δ-, and metabotropic glutamate receptors. Purkinje cells receive two excitatory inputs, the parallel and climbing fibers; the combined effect of stimulation of these two inputs is to produce long-term depression of parallel fiber/Purkinje cell neurotransmission. Distribution of glutamate receptors in these two synapse populations in rat cerebella was studied using preembedding immunocytochemistry with antibodies to GluR1, GluR2/3, GluR5-7, NR1, δ1/2, and mGluR1α. Moderate/dense postsynaptic staining was most frequent in postsynaptic densities and spines of both parallel and climbing fiber synapses with mGluR1α antibody, was intermediate in frequency with GluR2/3 and GluR5-7 antibodies, and was least frequent with GluR1 and NR1 antibodies. The most striking finding was the absence of significant postsynaptic staining with δ1/2 antibody in climbing fiber synapses in adult animals, even though postsynaptic staining was prevalent in parallel fiber synapses with this antibody. In contrast to adults, moderate/dense postsynaptic immunolabeling of climbing fiber synapses with δ1/2 antibody was common in rats at 10 days postnatal. This study provides direct morphological evidence that δ-glutamate receptors are differentially targeted to synapse populations. Our results support previous suggestions that δ2 is involved in development of parallel and climbing fiber synapses and in long-term depression of parallel fiber/Purkinje synaptic responses in adults.     

Reliability of Computation in the Cerebellum

The mossy fiber-granule cell-parallel fiber-Purkinje cell system of the cerebellar cortex is investigated from the viewpoint of reliability of computation. It is shown that the effects of variability in the inputs to a Purkinje cell can be reduced by having a large number of parallel fibers whose activities are statistically independent. The mossy fiber-granule cell relay is shown to be capable of performing the required function of transforming the activity in a small number of mossy fibers into activity in a much larger number of parallel fibers, while ensuring that there is little correlation between the activities of individual parallel fibers. The effects of variability in the outputs of Purkinje cells may be reduced by redundancy and convergence schemes, as evidenced by the geometrical pattern of parallel fibers and Purkinje cells and the convergence of these cells onto their target neurons.     

Effect of harmaline on the complex spike shape and depression time in cerebellar Purkinje cell discharge in rat postnatal ontogenesis

Functional relationship between wave form of complex spike (CS) and depression time of simple spike (SS) in discharge of cerebellar Purkinje cells was studied after their activation with afferent climbing fiber at different terms of postnatal ontogenesis in norm and after treatment with harmaline. The experiments were carried out on three age groups of Wistar rats: rat pups (2 weeks), the adult (4–6 months), and the old animals (22–26 months). It was established that the SS duration in norm was approximately equal in rat pups, adult, and old animals, whereas it markedly decreased form the young to the old animals during the SS depression in the Purkinje cell discharge. Frequency of small action potential (lAP) and their number in the Purkinje cell discharge were approximately equal in young rat pups and adult animals, while in old animals these parameters were higher, on average, by 30%. After administration of harmaline, all CS parameters in rat pups and old animals increased in parallel with the depression time elongation. In adult rats, harmaline did not produce statistically significant changes of the mean values of CS parameters, but an increase of the simple spike depression time was observed. The obtained results allow concluding that the SS wave form and the simple spike depression time in norm are functionally coupled and change with age. The effect of harmaline on the CS wave forms as well as on interrelation of the CS duration and the CS depression time in the Purkinje cell discharge was more pronounced at the early and the late stages of Wistar rat postnatal ontogenesis.     

Adaptive filter model of the cerebellum

The Marr-Albus model of the cerebellum has been reformulated with linear system analysis. This adaptive linear filter model of the cerebellum performs a filtering action of a phase lead-lag compensator with learning capability, and will give an account for the phenomena which have been termed cerebellar compensation. It is postulated that a Golgi cell may act as a phase lag element; for example, as a leaky integrator with time constant about several seconds. Under this assumption, a mossy fiber-granule cell-Golgi cell input network functions as a phase lead-lag compensator. Output signals from Golgi-granule cell systems, namely, parallel fiber signals, are gathered together through variable synaptic connections to form a Purkinje cell output. From a general theory of adaptive linear filters, learning principles for these modifiable connections are derived. By these learning principles, a Purkinje cell output converges to the desired response to minimize the mean square error of the performance. In a more general sense, a Purkinje cell acquires a filtering function on the basis of multiple pairs of input signals and corresponding desired output signals. The mode of convergence of the output signal is described when the input signal is sinusoidal.     

Effects of active versus passive dendritic membranes on the transfer properties of a simulated neuron

In a simulated neuron with a dendritic tree, the relative effects of active and passive dendritic membranes on transfer properties were studied. The simulations were performed by means of a digital computer. The computations calculated the changes in transmembrane voltages of many compartments over time as a function of other biophysical variables. These variables were synaptic input intensity, critical firing threshold, rate of leakage of current across the membrane, and rate of longitudinal current spread between compartments. For both passive and active dendrites, the transfer properties of the soma studied for different rates of longitudinal current spread. With low rates of current spread, graded changes in firing threshold produced correspondingly graded changes in output discharge. With high rates of current spread, the neuron became a bistable operator where spiking was enhanced if the threshold was below a certain level and suppressed if the threshold was above that level. Since alterations in firing threshold were shown to have the same effect on firing rate as alterations in synaptic input intensity, the neuron can be said to change from graded to contrast-enhancing in its response to stimuli of different intensities. The presence or absence of dendritic spiking was found to have a significant effect on the integrative properties of the simulated neuron. In particular, contrast enhancement was considerably more pronounced in neurons with passive than with active dendrites in that somatic spike rates reached a higher maximum when dendrites were passive. With active dendrites, a less intense input was needed to initiate somatic spiking than with passive dendrites because a distal dendritic spike could easily propagate by means of longitudinal current spread to the soma. Once somatic spiking was initiated, though, spike rates tended to be lower with active than with passive dendrites because the soma recovered more slowly from its post-spike refractory period if it was also influenced by refractory periods in the dendrites. The experiment of comparing neurons with active and passive dendrites was repeated at a different, higher value of synaptic input. The same differences in transfer properties between the active and passive cases emerged as before. Spiking patterns in neurons with active dendrites were also affected by the time distribution of synaptic inputs. In a previous study, inputs had been random over both space and time, varying about a predetermined mean, whereas in the present study, inputs were random over space but uniform over time. When inputs were made uniform over time, spiking became more difficult to initiate and the transition from graded to bistable response became less sharp.     

Dynamics of the Instantaneous Firing Rate in Response to Changes in Input Statistics

We review and extend recent results on the instantaneous firing rate dynamics of simplified models of spiking neurons in response to noisy current inputs. It has been shown recently that the response of the instantaneous firing rate to small amplitude oscillations in the mean inputs depends in the large frequency limit f on the spike initiation dynamics. A particular simplified model, the exponential integrate-and-fire (EIF) model, has a response that decays as 1/f in the large frequency limit and describes very well the response of conductance-based models with a Hodgkin-Huxley type fast sodium current. Here, we show that the response of the EIF instantaneous firing rate also decays as 1/f in the case of an oscillation in the variance of the inputs for both white and colored noise. We then compute the initial transient response of the firing rate of the EIF model to a step change in its mean inputs and/or in the variance of its inputs. We show that in both cases the response speed is proportional to the neuron stationary firing rate and inversely proportional to a spike slope factor _T that controls the sharpness of spike initiation: as 1/_T for a step change in mean inputs, and as 1/_T² for a step change in the variance in the inputs.     

Desynchronization of multivesicular release enhances Purkinje cell output

The release of neurotransmitter-filled vesicles after action potentials occurs with discrete time courses: submillisecond phasic release that can be desynchronized by activity followed by "delayed release" that persists for tens of milliseconds. Delayed release has a well-established role in synaptic integration, but it is not clear whether desynchronization of phasic release has physiological consequences. At the climbing fiber to Purkinje cell synapse, the synchronous fusion of multiple vesicles is critical for generating complex spikes. Here we show that stimulation at physiological frequencies drives the temporal dispersion of vesicles undergoing multivesicular release, resulting in a slowing of the EPSC on the millisecond timescale. Remarkably, these changes in EPSC kinetics robustly alter the Purkinje cell complex spike in a manner that promotes axonal propagation of individual spikelets. Thus, desynchronization of multivesicular release enhances the precise and efficient information transfer by complex spikes.     

Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells

Brief depolarization of cerebellar Purkinje cells was found to inhibit parallel fiber and climbing fiber EPSCs for tens of seconds. This depolarization-induced suppression of excitation (DSE) is accompanied by altered paired-pulse plasticity, suggesting a presynaptic locus. Fluorometric imaging revealed that postsynaptic depolarization also reduces presynaptic calcium influx. The inhibition of both presynaptic calcium influx and EPSCs is eliminated by buffering postsynaptic calcium with BAPTA. The cannabinoid CB1 receptor antagonist AM251 prevents DSE, and the agonist WIN 55,212-2 occludes DSE. These findings suggest that Purkinje cells release endogenous cannabinoids in response to elevated calcium, thereby inhibiting presynaptic calcium entry and suppressing transmitter release. DSE may provide a way for cells to use their firing rate to dynamically regulate synaptic inputs. Together with previous studies, these findings suggest a widespread role for endogenous cannabinoids in retrograde synaptic inhibition.     

Cerebellar Nuclear Neurons Use Time and Rate Coding to Transmit Purkinje Neuron Pauses

Neurons of the cerebellar nuclei convey the final output of the cerebellum to their targets in various parts of the brain. Within the cerebellum their direct upstream connections originate from inhibitory Purkinje neurons. Purkinje neurons have a complex firing pattern of regular spikes interrupted by intermittent pauses of variable length. How can the cerebellar nucleus process this complex input pattern? In this modeling study, we investigate different forms of Purkinje neuron simple spike pause synchrony and its influence on candidate coding strategies in the cerebellar nuclei. That is, we investigate how different alignments of synchronous pauses in synthetic Purkinje neuron spike trains affect either time-locking or rate-changes in the downstream nuclei. We find that Purkinje neuron synchrony is mainly represented by changes in the firing rate of cerebellar nuclei neurons. Pause beginning synchronization produced a unique effect on nuclei neuron firing, while the effect of pause ending and pause overlapping synchronization could not be distinguished from each other. Pause beginning synchronization produced better time-locking of nuclear neurons for short length pauses. We also characterize the effect of pause length and spike jitter on the nuclear neuron firing. Additionally, we find that the rate of rebound responses in nuclear neurons after a synchronous pause is controlled by the firing rate of Purkinje neurons preceding it.