Ali, R.B.; (2009) Glutamate and GABA receptors in cerebellar granule cells. Doctoral thesis , UCL (University College London).

Abstract

This study aimed at providing a clearer understanding of the functional significance of specific receptor subtypes in inhibitory and excitatory synaptic transmission in cerebellar granule cells. These cells have a simple morphology, typically consisting of a small soma with four short dendrites. Each receives a single excitatory input, which activates both AMPA and NMDA receptors. Granule cells also receive GABA-mediated inhibitory input from several Golgi cells. I have used mainly patch-clamp recording methods combined with use of pharmacological tools. Various strategies (examination of developmental changes, and use of transgenic animals) have been used to provide information about the importance of specific NMDA-, AMPA' and GABM receptor subunits in the transmission process. I examined developmental changes (~P8 to P60) in the contribution of NMDARs to mossy-fibre-to granule cell (MF-GC) synaptic currents in young and mature mice. Initial data suggested that NMDAR-mediated component was absent from quantal events recorded at mature synapses in these cells. I have used a number of different approaches to determine whether this can be explained by a lack of synaptic MDARS at the mature synapse. We investigated the importance of the two glutamate receptor subunits that are crucial to excitatory transmission in cerebellar granule cells - namely NR1, and GluR4. We used NR1 lox and GluR4lox mice, respectively, for these experiments. The data suggest that deletion of GluR4 may produce a compensatory change, consistent with the view that GluR4-containing AMPARS are important for transmission at the MF-GC synapse. Deletion of NR1 caused no compensatory change. We investigated a GABAA receptor subunit that is thought to be inhibitory transmission in these cells. Knockout of the gamma-2 subunit, caused a loss of IPSCs in these cells. However, there was no compensatory increase in tonic conductance. Furthermore, there was no compensatory change in intrinsic membrane properties in these cells. We also found no compensatory change in Purkinje cell firing. Thus any compensation, if present, must arise before the final output by Purkinje cells is completed.

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