GABA-A Receptors in the Amygdala: Distribution in the Normal and Alzheimer's Disease Human Brain

Abstract

GABAergic neurotransmission in the amygdala plays a crucial role in mediating emotional learning and memory. Alzheimer's disease (AD) is a neurodegenerative disease which leads to progressive loss of memory and psychiatric behavioural changes. The amygdala is one of the earliest structures to undergo atrophy in AD but the extent of GABAergic changes in the amygdala in AD are still unknown. This thesis set out to investigate the GABAA (γ-aminobutyric acid type A) receptor subunit organisation in the human amygdala and examine whether expression of subunits changes in the AD human amygdala. The detailed regional, cellular, and subcellular expression of GABAA receptor subunits α1, α2, α3, β2,3, and γ2 were characterised using single-, double-, and triple-immunohistochemical labelling within the postmortem normal human amygdala. The expression of GABAA receptor subunits in the post-mortem intermediate- and late-stage (Braak IV–VI) AD human amygdala (n = 7) was compared to age-matched controls (n = 6) using optical densitometry. In the neurologically normal amygdala, the predominant GABAA receptor subtypes expressed are α1β2,3γ2, α2α3β2,3γ2, and α3β2,3γ2. The α1, α2, and α3 subunits show compartmentalised expression on six distinct cell populations in the normal human amygdala: type 1 aspiny cells are found abundantly in the basolateral nuclear group (BLNG) and express α1β2,3γ2 and glutamic acid decarboxylase isoforms 65/67 (GAD65/67); type 2 aspiny cells are found in the paralaminar nucleus (PL) and express α1β2,3γ2 and GAD65/67; type 3 aspiny cells are found sparsely in the BLNG and express α1β2,3γ2 and GAD65/67 was well as combination of calcium-binding proteins including parvalbumin (PV), calbindin (CB), and calretinin (CR); type 4 cells are spiny cells which express α2α3β2,3γ2 at high levels on proximal processes and do not express GAD65/67; type 5 cells are found in the central nucleus (CE) and express α2α3β2,3; and type 6 cells are found closely packed in the intercalated cell masses (ICM) and express α3/β2,3. In Alzheimer’s disease, there is significant GABAA receptor subunit loss in all nuclei of the amygdala except for the basomedial nucleus (BM), medial subregion of PL (PLm), posterior cortical nuclei (PCO), amygdalohippocampal transition area (AHI), CE, and posterior medial nucleus (MEp) (see schematic diagram below). In particular, the major loss of α1 and β2,3 subunits is found within the lateral nucleus (LA) and basolateral nucleus (BL). The α1 subunit is also significantly lost in the lateral subregion of the PL (PLl), anterior ME (MEa), and ICM. Loss of the α2 subunit is found in the ventral anterior cortical nucleus (ACOv) and loss of the α3 subunit is seen in the parahippocampal transition area (PHA). The γ2 subunit does not show significant loss. The reduction of GABAA receptor subunit expression may be implicated in the pathogenesis of AD in the human brain.