Ward, D.R.; (2012) Golgi cell mediated inhibition in the cerebellar granule cell layer. Doctoral thesis , UCL (University College London).

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Abstract

The cerebellar cortex integrates multimodal information from mossy fibre (MF) and climbing fibre inputs to perform a variety of computations relating to movement, motor learning and balance. Before MF information can be combined with climbing fibre input in Purkinje cells (PCs) it must pass through the granule cell (GrC) layer wherein it is transformed by the anatomical connectivity and local inhibitory circuit. GrCs receive both tonic and phasic inhibition, the latter arising from the release of gamma aminobutyric acid (GABA) from Golgi cell (GoC) axons. However, the properties of GoC mediated inhibition and its computational significance are not well understood. I have characterised the GoC–GrC synaptic connection using paired whole-cell patch-clamp recordings. My results show that unitary GoC inputs are smaller than previously realised and are frequently mediated purely by spillover from synapses onto adjacent GrCs. I have used the dynamic clamp method to investigate how changes in the frequency and synchrony of spiking in the GoC network can affect GrC computation. I found that changes in GoC firing rate strongly modulate the gain of the GrC input–output (I–O) function, while GoC synchrony can create permissive and non-permissive windows resulting in a patternation of GrC firing that may convey a temporal signal to downstream PCs. GoCs are subject to regulation through the activation of metabotropic glutamate receptors (mGluRs) and nicotinic acetylcholine receptors (nAChRs). I have investigated how these modulatory inputs to GoCs might affect their inhibitory output and show that mGluR activation dramatically reduces GABA release while nAChR activation dramatically increases GABA release from GoCs. My results show that GoCs can exert potent inhibitory control over GrCs that could be relevant to the processing of both temporally coded and rate coded information.

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