Reinoud Maex

Deletion of FMR1 in Purkinje cells enhances parallel fiber LTD, enlarges spines, and attenuates cerebellar eyelid conditioning in Fragile X syndrome.

Absence of functional FMRP causes Fragile X syndrome. Abnormalities in synaptic processes in the cerebral cortex and hippocampus contribute to cognitive deficits in Fragile X patients. So far, the potential roles of cerebellar deficits have not been investigated. Here, we demonstrate that both global and Purkinje cell-specific knockouts of Fmr1 show deficits in classical delay eye-blink conditioning in that the percentage of conditioned responses as well as their peak amplitude and peak velocity are reduced. Purkinje cells of these mice show elongated spines and enhanced LTD induction at the parallel fiber synapses that innervate these spines. Moreover, Fragile X patients display the same cerebellar deficits in eye-blink conditioning as the mutant mice. These data indicate that a lack of FMRP leads to cerebellar deficits at both the cellular and behavioral levels and raise the possibility that cerebellar dysfunctions can contribute to motor learning deficits in Fragile X patients.

Synchronization of Golgi and granule cell firing in a detailed network model of the cerebellar granule cell layer

The granular layer of the cerebellum has a disproportionately large number of excitatory (granule cells) versus inhibitory neurons (Golgi cells). Its synaptic organization is also unique with a dense reciprocal innervation between granule and Golgi cells but without synaptic contacts among the neurons of either population. Physiological recordings of granule or Golgi cell activity are scarce, and our current thinking about the way the granular layer functions is based almost exclusively on theoretical considerations. We computed the steady-state activity of a large-scale model of the granular layer of the rat cerebellum. Within a few tens of milliseconds after the start of random mossy fiber input, the populations of Golgi and granule cells became entrained in a single synchronous oscillation, the basic frequency of which ranged from 10 to 40 Hz depending on the average rate of firing in the mossy fiber population. The long parallel fibers ensured, through alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-mediated synapses, a coherent excitation of Golgi cells, while the regular firing of each Golgi cell synchronized all granule cells within its axonal radius through transient activation of their gamma-aminobutyric acid-A (GABAA) receptor synapses. Individual granule cells often remained silent during a few successive oscillation cycles so that their average firing rates, which could be quite variable, reflected the average activities of their mossy fiber afferents. The synchronous, rhythmic firing pattern was robust over a broad range of biologically realistic parameter values and to parameter randomization. Three conditions, however, made the oscillations more transient and could desynchronize the entire network in the end: a very low mossy fiber activity, a very dominant excitation of Golgi cells through mossy fiber synapses (rather than through parallel fiber synapses), and a tonic activation of granule cell GABAA receptors (with an almost complete absence of synaptically induced inhibitory postsynaptic currents). These three conditions were associated with a reduction in the parallel fiber activity, and synchrony could be restored by increasing the mossy fiber firing rate. The model predicts that, under conditions of strong mossy fiber input to the cerebellum, Golgi cells do not only control the strength of parallel fiber activity but also the timing of the individual spikes. Provided that their parallel fiber synapses constitute an important source of excitation, Golgi cells fire rhythmically and synchronized with granule cells over large distances along the parallel fiber axis. According to the model, the granular layer of the cerebellum is desynchronized when the mossy fiber firing rate is low.

Synaptic pathways in neural microcircuits

The functions performed by different neural microcircuits depend on the anatomical and physiological properties of the various synaptic pathways connecting neurons. Neural microcircuits across various species and brain regions are similar in terms of their repertoire of neurotransmitters, their synaptic kinetics, their short-term and long-term plasticity, and the target-specificity of their synaptic connections. However, microcircuits can be fundamentally different in terms of the precise recurrent design used to achieve a specific functionality. In this review, which is part of the TINS Microcircuits Special Feature, we compare the connectivity designs in spinal, hippocampal, neocortical and cerebellar microcircuits, and discuss the different computational challenges that each microcircuit faces.

Inactivation of Calcium-Binding Protein Genes Induces 160 Hz Oscillations in the Cerebellar Cortex of Alert Mice

Oscillations in neuronal populations may either be imposed by intrinsically oscillating pacemakers neurons or emerge from specific attributes of a distributed network of connected neurons. Calretinin and calbindin are two calcium-binding proteins involved in the shaping of intraneuronal Ca2+ fluxes. However, although their physiological function has been studied extensively at the level of a single neuron, little is known about their role at the network level. Here we found that null mutations of genes encoding calretinin or calbindin induce 160 Hz local field potential oscillations in the cerebellar cortex of alert mice. These oscillations reached maximum amplitude just beneath the Purkinje cell bodies and are reinforced in the cerebellum of mice deficient in both calretinin and calbindin. Purkinje cells fired simple spikes phase locked to the oscillations and synchronized along the parallel fiber axis. The oscillations reversibly disappeared when gap junctions or either GABAA or NMDA receptors were blocked. Cutaneous stimulation of the whisker region transiently suppressed the oscillations. However, the intrinsic somatic excitability of Purkinje cells recorded in slice preparation was not significantly altered in mutant mice. Functionally, these results suggest that 160 Hz oscillation emerges from a network mechanism combining synchronization of Purkinje cell assemblies through parallel fiber excitation and the network of coupled interneurons of the molecular layer. These findings demonstrate that subtle genetically induced modifications of Ca2+ homeostasis in specific neuron types can alter the observed dynamics of the global network.

Oscillations in the cerebellar cortex: a prediction of their frequency bands.

Local recurrent connections endow the cerebellar cortex with an intrinsic dynamics. We performed computer simulations to predict the frequency bands of the oscillations that will most likely emerge. Feedback inhibition from the Golgi to the granule cells induced 10-50 Hz oscillations, the period at resonance being approximately equal to four times the maximum conduction delay generated along the parallel-fiber connections from granule to Golgi cells. In the molecular layer, the interneurons tended to induce fast oscillations (100-250 Hz), having a period equal to about four times the delay over their reciprocal synaptic connections. Finally, although the presence of lateral inhibition among the Purkinje cells has not been firmly established, reciprocal Purkinje-cell synapses are predicted to transform the cerebellar cortex into a potential temporal integrator.

The function of cerebellar Golgi cells revisited.

The inhibitory interneurons of the cerebellar cortex have received very little attention compared to the granule and Purkinje cells, and Golgi cells are no exception. Theoretical considerations of the function of Golgi cell functions have evolved little since from the late sixties and experimental studies were sparse until the last few years. Recent modeling and in vivo experimental studies by our group, combined with in vitro experimental studies by others, have provided new insights into the properties of these cells which necessitate a revisiting of their function. The connectivity of the Golgi cell The anatomical facts are rather simple. The numerically most important input to the cerebellum is the mossy fiber system (Murphy and Sabah, 1971; Brodal and Bjaalie, 1997). If we limit ourselves to this input, the anatomy of cerebellar cortex can be described as a two-layered network. The input layer, corresponding to the granular layer, processes the incoming mossy fiber signals and transmits them by the parallel fiber system to the output layer, consisting mainly of the Purkinje cells. In both layers activity is controlled by inhibitory neurons, the Golgi cells in the input layers, and the basket and stellate cells in the output layer. Mossy fibers activate both the excitatory granule cells and the inhibitory Golgi cells (Fig. 1A). The granule cell axon forms the parallel fibers, which not only transmit information to the output layer, but also provide additional excitatory input to Golgi cells. Each Golgi cell in turns inhibits the many granule cells present within the range of its axonal arbor (Eccles et al., 1966) with probably some overlap between adjacent Golgi cells. The combination of the parallel fiber excitation of Golgi cells with their inhibition of granule cells constitutes a feedback inhibition circuit (Fig. 1C). The direct excitation of Golgi cells by mossy fibers (Fig. 1B) provides a feed-forward connection. It should be noted, however, that the existence of mossy fiber contacts onto Golgi cells couldwere not be confirmed found in electron microscopal reconstructions of cerebellar glomeruli (Jakab and Hamori, 1988).

Weak common parallel fibre synapses explain the loose synchrony observed between rat cerebellar Golgi cells

In anaesthetized rats, pairs of cerebellar Golgi cells fired synchronously at rest, provided they were aligned along the parallel fibre axis. The observed synchrony was much less precise, however, than that which would be expected to result from common, monosynaptic parallel fibre excitation. To explain this discrepancy, the precision and frequency of spike synchronization (i.e. the width and area of the central peak on the spike train cross‐correlogram) were computed in a generic model for varying input, synaptic and neuronal parameters. Correlation peaks between model neurons became broader, and peak area smaller, when the number of afferents increased and each single synapse decreased proportionally in strength. Peak width was inversely proportional to firing rate, but independent of the percentage of shared afferents. Peak area, in contrast, scaled with the percentage of shared afferents but was almost firing rate independent. Broad correlation peaks between pairs of model neurons resulted from the loose spike timing between single model neurons and their afferents. This loose timing reflected a need for long‐term synaptic integration to fire the neurons. Model neurons could accomplish this through firing rate adaptation mediated by a Ca2+‐activated K+ channel. We conclude that loose synchrony may be entirely explained by shared input from monosynaptic, non‐synchronized afferents. The inverse relationship between peak width and firing rate allowed us to distinguish common parallel fibre input from firing rate covariance as a primary cause of loose synchrony between cerebellar Golgi cells in anaesthetized rats.

The cerebellum: cortical processing and theory

Several advances over the past year have made necessary a complete re-evaluation of the function of the cerebellum and of the role of cerebellar synaptic plasticity. These advances include the discovery of parallel fiber induced long-term depression, the presence of normal motor coordination in the absence of cerebellar long-term depression in knock-out mice, and the strong activation of the cerebellar nuclei while sensory tasks are performed.

Dendritic amplification of inhibitory postsynaptic potentials in a model Purkinje cell

In neurons with large dendritic arbors, the postsynaptic potentials interact in a complex manner with active and passive membrane properties, causing not easily predictable transformations during the propagation from synapse to soma. Previous theoretical and experimental studies in both cerebellar Purkinje cells and neocortical pyramidal neurons have shown that voltage‐dependent ion channels change the amplitude and time‐course of postsynaptic potentials. We investigated the mechanisms involved in the propagation of inhibitory postsynaptic potentials (IPSPs) along active dendrites in a model of the Purkinje cell. The amplitude and time‐course of IPSPs recorded at the soma were dependent on the synaptic distance from the soma, as predicted by passive cable theory. We show that the effect of distance on the amplitude and width of the IPSP was significantly reduced by the dendritic ion channels, whereas the rise time was not affected. Somatic IPSPs evoked by the activation of the most distal synapses were up to six times amplified owing to the presence of voltage‐gated channels and the IPSP width became independent of the covered distance. A transient deactivation of the Ca2+ channels and the Ca2+‐dependent K+ channels, triggered by the hyperpolarization following activation of the inhibitory synapse, was found to be responsible for these dynamics. Nevertheless, the position of activated synapses had a marked effect on the Purkinje cell firing pattern, making stellate cells and basket cells most suitable for controlling the firing rate and spike timing, respectively, of their target Purkinje cells.

Peripheral stimuli excite coronal beams of Golgi cells in rat cerebellar cortex

Cerebellar granule cells constitute the largest neurone population of the brain. Their axons run as parallel fibres along the coronal axis, and the one-dimensional spread of excitation that is expected to result from this arrangement is a key assumption of theories of cerebellar function. In many studies using various techniques, however, it was not possible to evoke such a beam-like propagation of excitation with natural stimuli. We recorded, in Crus I and II of anaesthetised rats, pairs of Golgi cells aligned along the parallel fibre axis and synchronising spontaneously. Each pair was subjected to two stimulation protocols: punctate and semi-continuous. Local punctate facial stimulation evoked distinct fast and late responses of variable strength and latency (fast: 4.0-10.2 ms; late: 13.6-22.7 ms). Semi-continuous stimulation with a brush increased the firing rate, and modified the precision and phase of synchronisation. Differences between a pair in response strength and phase to brush stimulation correlated strongly with the difference in latency to punctate stimulation. These observations were reproduced in a model of the granular layer. The stimulus activated a central patch of mossy fibres, and Golgi cells received short- and long-range excitation from mossy and parallel fibres, respectively. The strength and latency of the punctate response of a model Golgi cell were found to vary with its position, reflecting a systematic change in the contribution of mossy and parallel fibres to its excitation with distance from the activated patch. During brush stimulation, model Golgi cells inside the patch fired more precisely synchronised, whereas the other Golgi cells responded with a lag proportional to their distance from the patch, thereby reproducing the experimentally observed changes in synchronisation. Taken together with the previously reported large receptive fields of Golgi cells and with their spontaneous synchronisation, the variable, position-dependent latency of evoked Golgi cell responses indicates a beam-like spread of excitation along the parallel fibres in rat cerebellar cortex.