GABA_AR expression in brain noradrenergic and serotonergic centres and their plasticity in the context of stress induced behaviours

Abstract

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_ARs may influence LC and DRN neuronal excitability. Therefore, within this thesis I localised distinct GABA_AR 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_AR alpha1 subunit was predominantly localised to the non-principal, putative interneurons of the LC and DRN, whereas the GABA_AR alpha2 and alpha3 subunits were mainly localised to the principal monoaminergic cells. This apparent segregation suggests that the precise targeting of certain GABA_AR 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_AR expression at the transcriptomic level, in a brain region and subunit specific manner and thus
provide evidence for an important role of the GABA_AR 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_AR
alpha3 subunit expression in the DRN, parallels adaptive-like behavioural
changes in response to a novel environment.

Date of Award	Oct 2013
Original language	English
Supervisor	Jerome Swinny (Supervisor) & Arthur Butt (Supervisor)