Wang, Shuaiyu; (2025) Distinct roles of somatodendritic and axonal Group I metabotropic glutamate receptors in modulating hippocampal granule cell excitability. Doctoral thesis (Ph.D), UCL (University College London).

Text PhD thesis Shuaiyu Wang.pdf - Accepted Version Access restricted to UCL open access staff until 1 March 2026. Download (6MB)

Abstract

The hippocampal dentate gyrus is critically involved in learning and memory. Granule cells are the principal neurons in the dentate gyrus. Granule cells receive glutamatergic afferents from cortical and hippocampal neurons. Endogenous glutamate activates ionotropic and metabotropic glutamate receptors (mGluRs) including Group I mGluRs. These consist of mGlu1 and mGlu5 subtypes. Group I mGluRs are promising drug targets for the treatment of cognitive disorders, yet little is known about how they modulate granule cell intrinsic activity. By making electrophysiological recordings from mature granule cells present in brain slices, I demonstrated that pharmacological activation of Group I mGluRs depolarized the resting membrane potential, enhanced the input resistance, induced an afterdepolarization following action potentials and reduced the spike threshold. The Group I mGluR effects on input resistance and spike threshold were irreversible upon washout. Consequently, granule cells excitability was enhanced. Endogenous glutamate release onto granule cells also activated Group I mGluRs to persistently decrease the spike threshold and augment excitability. The spike threshold plasticity was axon-dependent as it did not occur in neurons with severed axons. Immunogold labelling coupled with electron microscopy confirmed that mGlu1 subunits were expressed on axons and soma-dendrites. The spike threshold plasticity was due to axonal mGlu1 receptors activating CaV3.2 Ca2+ channels to elevate [Ca2+]i, which subsequently inhibited KV7 channels. Surprisingly, these axonal effects were G-protein independent. In contrast, somato-dendritic effects were due to Group I mGluRs activating G-proteins to inhibit GIRK channels. Finally, I showed that mGlu1 receptor-induced spike threshold plasticity enhanced EPSP-spike coupling. Altogether, my data strongly suggest that Group I mGluRs are located in axons where they play a crucial role in modifying the spike threshold and action potential firing. My findings also suggest that Group I mGluRs present in soma-dendrites and axons are coupled to distinct signaling pathways. These findings may inform drug design for treating cognitive disorders.

Download activity - last month

Export as XMLCSVJSON

Download activity - last 12 months

Export as XMLCSVJSON

Downloads by country - last 12 months

Export as XMLJSONCSV

Archive Staff Only

View Item