Behavioural phenotyping of mice with genetic alterations of the GABA[subscript A] receptor

Abstract

GABA is the main inhibitory neurotransmitter of the central nervous system. GABA[subscript A]Rs are multimeric transmembrane receptors, which are composed of 5 subunits. It is known that there are 19 subunits that can make up the GABA[subscript A]Rs, allowing for a vast array of receptor subtypes. In addition to the GABA binding site GABA[subscript A]Rs have distinct allosteric binding sites for benzodiazepines, barbiturates, ethanol, certain general anaesthetics and neuroactive steroids. The molecular heterogeneity of the GABA[subscript A]R is accompanied by distinct pharmacological profiles of the different receptor subtypes. The advance of transgenic mouse models has allowed the functional significance of this heterogeneity to be studied in vivo. Therefore, this thesis utilises a variety of transgenic mouse models carrying either mutations or deletions of certain subunits to study the functional significance of the receptor heterogeneity.

Mice lacking the α1 subunit (α1[superscript(-/-)]), carrying a point mutation of the α1 subunit (α1H101R), and mice lacking the δ subunit (δ[superscript(-/-)]) have been utilised to investigate the role of these subunits in the sedative actions of benzodiazepines and the GABA[subscript A]R agonist THIP. Although there are limitations to the interpretation of these results due genetic background of the α1[superscript(-/-)] and α1H101R, experiments suggest that the α1H101R mutation is not behaviourally silent as previously suggested and provide further evidence that the α1 subunit mediates the sedative properties of benzodiazepines. These experiments also reveal that the extrasynaptic δ containing receptors are responsible for mediating the sedative effects of THIP, and these findings combined with evidence from collaborators, implicates the thalamus as an anatomical mediator of these effects.

An investigation of the putative cognitive enhancing effects of THIP using an attentional set-shifting task for mice suggested that pre-treatment with THIP reduces the number of errors to reach criterion. δ[superscript(-/-)] mice could not be trained to perform the task, therefore further behavioural investigation of these mice was performed, which suggested a heightened level of anxiety and reduced motivation for a food reward.

This thesis has furthered our understanding of the functional role of GABA[subscript A]R subtypes. With the advance in genetic manipulations that allow for regionally selective mutations of the receptor the anatomical structures involved in these functions can be identified.