The broad intention of this thesis was to understand which factors regulate the release of serotonin and noradrenaline throughout the brain. Multiple factors, such as ion channels, transporters and neurotransmitter receptors shape the release of serotonin and noradrenaline within strict spatial and temporal windows. I was interested in how fast inhibition mediated by GABA<sub>A</sub>Rs may influence LC and DRN neuronal excitability. Therefore, within this thesis I localised distinct GABA<sub>A</sub>R subunits to the cellular and sub-cellular compartments of neurochemically diverse cell types which comprise the networks of two major monoaminergic brain centres, the noradrenergic Locus Coeruleus (LC) and the serotonergic Dorsal Raphe Nucleus (DRN). The GABA<sub>A</sub>R alpha1 subunit was predominantly localised to the non-principal, putative interneurons of the LC and DRN, whereas the GABA<sub>A</sub>R alpha2 and alpha3 subunits were mainly localised to the principal monoaminergic cells. This apparent segregation suggests that the precise targeting of certain GABA<sub>A</sub>R subunits to different cellular and sub-cellular compartments is important for shaping LC and DRN neuronal excitability, and thus the release of noradrenaline and serotonin. As these monoaminergic systems are engaged by stressor exposure (Swinny et al., 2010, Kirby et al., 2000, Kirby et al., 2007), and as they have been shown to have an important role in shaping mood (Stockmeier et al., 1998, Baumann et al., 2002), I was also interested to understand whether stressors engaged the GABAergic system to influence the release of monoamines. Moreover, I have demonstrated that a mild repeated stressor influences GABA<sub>A</sub>R expression at the transcriptomic level, in a brain region and subunit specific manner and thus provide evidence for an important role of the GABA<sub>A</sub>R alpha3 subunit in the processing of stressor related information via the DRN. The finding that the stress neuropeptide CRH, contacts putative inhibitory synapses of serotonergic and non-serotonergic neurons of the DRN provides further evidence for the potential role of GABAergic neurotransmission in shaping DRN neuronal excitability in response to stressors. Finally, through behavioural phenotyping I have been able to demonstrate that a stressor induced increase in GABA<sub>A</sub>R alpha3 subunit expression in the DRN, parallels adaptive-like behavioural changes in response to a novel environment.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:617821 |
| Date | January 2013 |
| Creators | Corteen, Nicole |
| Contributors | Swinny, Jerome Dominic ; Butt, Arthur Morgan |
| Publisher | University of Portsmouth |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://researchportal.port.ac.uk/portal/en/theses/gabaar-expression-in-brain-noradrenergic-and-serotonergic-centres-and-their-plasticity-in-the-context-of-stress-induced-behaviours(ea7ac936-f020-46e8-9098-ee71bc6eff5d).html |
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