Mossy Fiber-granule Cell Relay Research Articles

Regulation of output spike patterns by phasic inhibition in cerebellar granule cells.

The complex interplay of multiple molecular mechanisms taking part to synaptic integration is hard to disentangle experimentally. Therefore, we developed a biologically realistic computational model based on the rich set of data characterizing the cerebellar glomerulus microcircuit. A specific issue was to determine the relative role of phasic and tonic inhibition in dynamically regulating granule cell firing, which has not been clarified yet. The model comprised the excitatory mossy fiber—granule cell and the inhibitory Golgi cell—granule cell synapses and accounted for vesicular release processes, neurotransmitter diffusion and activation of different receptor subtypes. Phasic inhibition was based on stochastic GABA release and spillover causing activation of two major classes of postsynaptic receptors, α1 and α6, while tonic inhibition was based on steady regulation of a Cl− leakage. The glomerular microcircuit model was validated against experimental responses to mossy fiber bursts while metabotropic receptors were blocked. Simulations showed that phasic inhibition controlled the number of spikes during burst transmission but predicted that it specifically controlled time-related parameters (firing initiation and conclusion and first spike precision) when the relative phase of excitation and inhibition was changed. In all conditions, the overall impact of α6 was larger than that of α1 subunit-containing receptors. However, α1 receptors controlled granule cell responses in a narrow ±10 ms band while α6 receptors showed broader ±50 ms tuning. Tonic inhibition biased these effects without changing their nature substantially. These simulations imply that phasic inhibitory mechanisms can dynamically regulate output spike patterns, as well as calcium influx and NMDA currents, at the mossy fiber—granule cell relay of cerebellum without the intervention of tonic inhibition.

Integration and regulation of glomerular inhibition in the cerebellar granular layer circuit.

Inhibitory synapses can be organized in different ways and be regulated by a multitude of mechanisms. One of the best known examples is provided by the inhibitory synapses formed by Golgi cells onto granule cells in the cerebellar glomeruli. These synapses are GABAergic and inhibit granule cells through two main mechanisms, phasic and tonic. The former is based on vesicular neurotransmitter release, the latter on the establishment of tonic γ-aminobutyric acid (GABA) levels determined by spillover and regulation of GABA uptake. The mechanisms of post-synaptic integration have been clarified to a considerable extent and have been shown to differentially involve α1 and α6 subunit-containing GABA-A receptors. Here, after reviewing the basic mechanisms of GABAergic transmission in the cerebellar glomeruli, we examine how inhibition controls signal transfer at the mossy fiber-granule cell relay. First of all, we consider how vesicular release impacts on signal timing and how tonic GABA levels control neurotransmission gain. Then, we analyze the integration of these inhibitory mechanisms within the granular layer network. Interestingly, it turns out that glomerular inhibition is just one element in a large integrated signaling system controlled at various levels by metabotropic receptors. GABA-B receptor activation by ambient GABA regulates glutamate release from mossy fibers through a pre-synaptic cross-talk mechanisms, GABA release through pre-synaptic auto-receptors, and granule cell input resistance through post-synaptic receptor activation and inhibition of a K inward-rectifier current. Metabotropic glutamate receptors (mGluRs) control GABA release from Golgi cell terminals and Golgi cell input resistance and autorhythmic firing. This complex set of mechanisms implements both homeostatic and winner-take-all processes, providing the basis for fine-tuning inhibitory neurotransmission and for optimizing signal transfer through the cerebellar cortex.

The cerebellar Golgi cell and spatiotemporal organization of granular layer activity.

The cerebellar granular layer has been suggested to perform a complex spatiotemporal reconfiguration of incoming mossy fiber signals. Central to this role is the inhibitory action exerted by Golgi cells over granule cells: Golgi cells inhibit granule cells through both feedforward and feedback inhibitory loops and generate a broad lateral inhibition that extends beyond the afferent synaptic field. This characteristic connectivity has recently been investigated in great detail and been correlated with specific functional properties of these neurons. These include theta-frequency pacemaking, network entrainment into coherent oscillations and phase resetting. Important advances have also been made in terms of determining the membrane and synaptic properties of the neuron, and clarifying the mechanisms of activation by input bursts. Moreover, voltage sensitive dye imaging and multi-electrode array (MEA) recordings, combined with mathematical simulations based on realistic computational models, have improved our understanding of the impact of Golgi cell activity on granular layer circuit computations. These investigations have highlighted the critical role of Golgi cells in: generating dense clusters of granule cell activity organized in center-surround structures, implementing combinatorial operations on multiple mossy fiber inputs, regulating transmission gain, and cut-off frequency, controlling spike timing and burst transmission, and determining the sign, intensity and duration of long-term synaptic plasticity at the mossy fiber-granule cell relay. This review considers recent advances in the field, highlighting the functional implications of Golgi cells for granular layer network computation and indicating new challenges for cerebellar research.

The spatial organization of long-term synaptic plasticity at the input stage of cerebellum.

The spatial organization of long-term synaptic plasticity [long-term potentiation (LTP) and long-term depression (LTD)] is supposed to play a critical role for distributed signal processing in neuronal networks, but its nature remains undetermined in most central circuits. By using multielectrode array recordings, we have reconstructed activation maps of the granular layer in cerebellar slices. LTP and LTD induced by theta-burst stimulation appeared in patches organized in such a way that, on average, LTP was surrounded by LTD. The sign of long-term synaptic plasticity in a given granular layer region was directly correlated with excitation and inversely correlated with inhibition: the most active areas tended to generate LTP, whereas the least active areas tended to generate LTD. Plasticity was almost entirely prevented by application of the NMDA receptor blocker, APV. This suggests that synaptic inhibition, through a control of membrane depolarization, effectively regulates NMDA channel unblock, postsynaptic calcium entry, and the induction of bidirectional synaptic plasticity at the mossy fiber-granule cell relay (Gall et al., 2005). By this mechanism, LTP and LTD could regulate the geometry and contrast of network computations, preprocessing the mossy fiber input to be conveyed to Purkinje cells and molecular layer interneurons.

Integrated regulation of signal coding and plasticity by NMDA receptors at a central synapse.

The role of NMDA and non-NMDA glutamate receptors in long-term potentiation has been intensely investigated, yet recent evidence on the dynamics of synaptic depolarization suggests that the original view should be extended. NMDA receptor-mediated currents, apart from their Ca2+ permeability, show a marked voltage dependence, consisting of current increase and slowdown during membrane depolarization. During highfrequency synaptic transmission, NMDA current increase and slowdown are primed by non-NMDA receptor-dependent depolarization and proceed regeneratively. Thus, NMDA receptors make a decisive contribution to membrane depolarization and spike-firing. From the data obtained at the mossy fiber- granule cell synapse of the cerebellum, we propose that the electrogenic role of NMDA receptors is functional to LTP induction. Moreover, during LTP, both NMDA and non- NMDA receptor currents are potentiated, thus establishing a feed-forward mechanism that ultimately enhances spike firing. Thus, NMDA receptors exert an integrated control on signal coding and plasticity. This mechanism may have important implications for information processing at the cerebellar mossy fibergranule cell relay.

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.