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Investigating the role of GABAA Receptor α1 and α2 Subunits in Synapse Formation

Arama, JE; (2015) Investigating the role of GABAA Receptor α1 and α2 Subunits in Synapse Formation. Doctoral thesis , UCL (University College London). Green open access

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Abstract

GABAA receptors, the essential functional components of the inhibitory synapses in the brain, have recently been demonstrated to play a structural role during synapse formation. The subunit composition of these receptors is known to determine their synaptic localization, but how different receptor subunits influence the formation of inhibitory synapses is currently unknown. The first aim of my thesis was to investigate whether these synaptogenic effects of GABAARs may be mediated by their large N-terminal extracellular domains. I have cloned, expressed and purified the N-terminal extracellular domains of the α1 and α2 subunits of GABAA receptors using the baculovirus/Sf9 cell system. When added to the GABAergic medium spiny neurones over a period of 14 days in vitro, these proteins were able to adhere to the cell surface and promote GABAergic synapse formation. As I was interested to study the molecular mechanisms that could mediate such effects, I used proteomics and mass spectrometry to search for potential trans-synaptic interacting proteins of α1 or α2 subunits which could bind specifically to the N-terminal extracellular domains of these subunits. In parallel, I have investigated how the activity of GABAA receptors influences the proper positioning and the assembly of inhibitory synapses in primary cultures of medium spiny neurones. In these experiments, GABAA receptor activity was blocked over the time period of 7 or 14 days in culture and cell survival, as well as the inhibitory synapse formation, were assessed. I have observed very specific structural changes in the density and distribution of α1- or α2-containing synapses under these conditions. My results indicate that the activity of GABAA receptors plays a central role in the formation and maintenance of different types of inhibitory synapses formed between GABAergic neurones during development.

Type: Thesis (Doctoral)
Title: Investigating the role of GABAA Receptor α1 and α2 Subunits in Synapse Formation
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
URI: http://discovery.ucl.ac.uk/id/eprint/1470759
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