Arlt, C; (2017) Principles of excitatory and inhibitory functional connectivity in cerebellar cortex in vivo. Doctoral thesis , UCL (University College London).

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Abstract

Determining the functional impact of single interneurons on neuronal output, and how interneurons are recruited by physiological patterns of excitation, are crucial to our understanding of inhibition. In the cerebellar cortex, molecular layer interneurons and their targets, Purkinje cells, receive excitatory inputs from granule cells and climbing fibres, the latter signalling to interneurons via glutamate spillover. How these feed-forward pathways are engaged by physiological patterns of activity in vivo is insufficiently understood. Using dual patch-clamp recordings from interneurons and Purkinje cells in mice in vivo, I have probed the spatiotemporal interactions between these circuit elements. I demonstrate that single spikes in single interneurons can potently inhibit the spiking of Purkinje cells. Granule cell input activates both interneurons and the Purkinje cells they inhibit, generating local feed-forward inhibition. Climbing fibre input activates interneurons via glutamate spillover, but only rarely activates interneurons that inhibit spiking of the same Purkinje cell receiving the climbing fibre input. Rather, by activating inhibition among interneurons, climbing fibre glutamate spillover results in delayed inhibition of interneurons controlling Purkinje cell spike output, forming a disinhibitory motif. Functional climbing fibre-interneuron inhibition, inhibition among interneurons, and interneuron-Purkinje cell inhibition are vertically organised in the molecular layer, providing an anatomical substrate for this microcircuit motif. During sensory processing, these motifs account for pathway-specific recruitment of interneurons, generating fast and delayed excitatory interneuron responses via the granule cell and climbing fibre pathway, respectively. Sensory stimulation recruits granule cell input into INs and PCs near-simultaneously, resulting in rapid feed-forward inhibition. Together, these findings quantify the functional impact of single interneurons on their targets in vivo, and reveal how granule cell and climbing fibre inputs differentially recruit inhibitory microcircuits to diversify cerebellar computations.

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