Short-Term Plasticity Combines with Excitation–Inhibition Balance to Expand Cerebellar Purkinje Cell Dynamic Range

Abstract

The balance between excitation (E) and inhibition (I) in neuronal networks controls the firing rate of principal cells through simple network organization, such as feedforward inhibitory circuits. Here, we demonstrate in male mice, that at the granule cell (GrC)-molecular layer interneuron (MLI)-Purkinje cell (PC) pathway of the cerebellar cortex, E/I balance is dynamically controlled by short-term dynamics during bursts of stimuli, shaping cerebellar output. Using a combination of electrophysiological recordings, optogenetic stimulation, and modeling, we describe the wide range of bidirectional changes in PC discharge triggered by GrC bursts, from robust excitation to complete inhibition. At high frequency (200 Hz), increasing the number of pulses in a burst (from 3 to 7) can switch a net inhibition of PC to a net excitation. Measurements of EPSCs and IPSCs during bursts and modeling showed that this feature can be explained by the interplay between short-term dynamics of the GrC-MLI-PC pathway and E/I balance impinging on PC. Our findings demonstrate that PC firing rate is highly sensitive to the duration of GrC bursts, which may define a temporal-to-rate code transformation in the cerebellar cortex. Sensorimotor information processing in the cerebellar cortex leads to the occurrence of a sequence of synaptic excitation and inhibition in Purkinje cells. Granule cells convey direct excitatory inputs and indirect inhibitory inputs to the Purkinje cells, through molecular layer interneurons, forming a feedforward inhibitory pathway. Using electrophysiological recordings, optogenetic stimulation, and mathematical modeling, we found that presynaptic short-term dynamics affect the balance between synaptic excitation and inhibition on Purkinje cells during high-frequency bursts and can reverse the sign of granule cell influence on Purkinje cell discharge when burst duration increases. We conclude that short-term dynamics may play an important role in transforming the duration of sensory inputs arriving on cerebellar granule cells into cerebellar cortical output firing rate.

Stellate cell computational modelling predicts signal filtering in the molecular layer circuit of cerebellum

“…During the stimulus trains, EPSCs showed an initial strong facilitation followed by depression (Fig. 5A, B) (Bao et al, 2010;Grangeray-Vilmint et al, 2018;Dorgans et al, 2019). The sequence of short-term facilitation and depression was the more evident the higher the stimulation frequency, suggesting that frequency-dependent short-term synaptic dynamics could regulate transmission efficacy along the PF -SC pathway (Mapelli et al, 2010).…”

Climbing Fibers Provide Graded Error Signals in Cerebellar Learning

“…Finally, and most importantly, the cellular mechanism of this short-term trial-by-trial learning is still unclear and how it correlates with long-term learning is unknown (Kimpo et al, 2014). Short-term plasticity of parallel fiber synapses and dendritic excitability plasticity may also be candidate mechanisms (Rancz and Häusser, 2006; Mathy et al, 2009; Ohtsuki et al, 2012; Regehr, 2012; Grangeray-Vilmint et al, 2018).…”

Short-term plasticity at cerebellar granule cell to molecular layer interneuron synapses expands information processing

“…At the input stage of the cerebellar cortex, a strategy based on the heterogeneity of STP across MF-GC synapses provides a mechanism for coding multisensory events at the level of single GCs (Chabrol et al, 2015). Also, differences in the profile of STP across synapses involved in the direct excitatory pathway or in the FFI microcircuit control the inhibitory/excitatory balance and shape Purkinje cell discharge (Grangeray-Vilmint et al, 2018). GCs which are the most numerous neurons in the brain, segregate in clonally related subpopulations (Espinosa and Luo, 2008).…”

“…Following compound stimulations of clusters of GCs or beams of parallel fibers (PFs), it was shown that GC-BC synapses depress during high-frequency stimulation while GC-SC synapses facilitate (Bao et al, 2010). By controlling the spatiotemporal excitability of PC (Bao et al, 2010), and potentially by shaping the inhibitory/excitatory balance (Grangeray-Vilmint et al, 2018), target cell–dependency of STP at the input stage of the FFI pathway must have important functional consequences for cerebellar output. However, target cell–dependency of STP at GC-MLI synapses is challenged by different experimental findings.…”