Abstract
Feedforward excitatory and inhibitory circuits regulate cerebellar output, but how these circuits interact to shape the somatodendritic excitability of Purkinje cells during motor behaviour remains unresolved. Here we perform dendritic and somatic patch-clamp recordings in vivo combined with optogenetic silencing of interneurons to investigate how dendritic excitation and inhibition generates bidirectional (that is, increased or decreased) Purkinje cell output during self-paced locomotion. We find that granule cells generate a sustained depolarization of Purkinje cell dendrites during movement, which is counterbalanced by variable levels of feedforward inhibition from local interneurons. Subtle differences in the dendritic excitation–inhibition balance generate robust, bidirectional changes in simple spike (SSp) output. Disrupting this balance by selectively silencing molecular layer interneurons results in unidirectional firing rate changes, increased SSp regularity and disrupted locomotor behaviour. Our findings provide a mechanistic understanding of how feedforward excitatory and inhibitory circuits shape Purkinje cell output during motor behaviour.
Highlights
Feedforward excitatory and inhibitory circuits regulate cerebellar output, but how these circuits interact to shape the somatodendritic excitability of Purkinje cells during motor behaviour remains unresolved
We show that granule cells (GCs) generate a sustained depolarization of Purkinje cells (PCs) dendrites during movement, which is counterbalanced by variable levels of feedforward inhibition (FFI) from molecular layer interneurons (MLIs)
The direction of simple spike (SSp) modulation during locomotion did not depend on the quiet wakefulness firing rate of individual PCs (r 1⁄4 À 0.02, P 1⁄4 0.91, n 1⁄4 38 from N 1⁄4 33 mice; Supplementary Fig. 2D,E)—that is, cells that displayed high firing rates during quiet wakefulness did not show a bias towards decreasing their firing rates during locomotion or vice versa[5]
Summary
Feedforward excitatory and inhibitory circuits regulate cerebellar output, but how these circuits interact to shape the somatodendritic excitability of Purkinje cells during motor behaviour remains unresolved. PCs—the axons of which constitute the sole output from the cerebellar cortex— receive strong feedforward inhibition (FFI) from molecular layer interneurons (MLIs)[11,14,15,16,17] This fast, direct inhibition opposes the effects of excitatory input from cerebellar granule cells (GCs) to modulate the rate and temporal dynamics of PC SSp output[15,18]. Model 3 describes the unidirectional but variable enhancement of FFE and FFI, the ratio of which dictates the magnitude and direction of PC SSp firing rate changes To test these synaptic input models in vivo, we combined dendritic and somatic patch-clamp recordings from PCs, optogenetic silencing of MLIs and quantitative behavioural analysis. Our findings provide a mechanistic understanding of how feedforward excitatory and inhibitory circuits regulate the somatodendritic excitability of PCs during self-paced motor behaviour
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