Age- and Sex-Specific Changes of the GABA Signalling Components in the Human Hippocampus

Abstract

Gamma-Aminobutyric Acid (GABA) is the primary inhibitory neurotransmitter in the nervous system. The GABAergic signalling system is composed of GABA synthesising enzymes (glutamic acid decarboxylases - GADs), GABA transporters (GATs) and specific GABA receptors (GABAA and GABAB receptors), which are formed by a conformation of different receptor subunits. Variation in the expression level function of these signalling components can affect the inhibitory capacity of GABA. Previous studies have shown changes in the expression of GABA signalling components, with increasing age and between sexes. However, most of these studies have been conducted in animal models and resulted in inconsistent findings. These studies also have not focussed on the hippocampus, which is a small region of the limbic system and is the primary memory centre of the brain. Hippocampal function has been shown to be impaired during ageing and age-related disorders such as Alzheimer's Disease (AD). Therefore, this study is the first analysis of age- and sex-specific differences in the expression of GABAA and GABAB receptor subunits and synthesizing enzymes in the human hippocampus and entorhinal cortex (ECx) using Western Blotting. The results show that the GABAergic system is relatively robust against age- and sex-specific differences in the human hippocampus. There were age-related decreases of the GABAA α1, β3 and GABABR R1 subunits in males and the GABABR R2 subunit in the dentate gyrus (DG) of the hippocampus in females. There was also an age-related increase in GABAAR α5 subunit expression in the ECx. We also observed sex-specific differences, with older females showing significantly higher expression of GABAAR β1 and GABABR R2 subunits in the DG of the hippocampus. Older females also showed increased expression of the GABAAR γ2 subunit in comparison to older males in the ECx. No significant age- and sex-specific differences were observed in GABA synthesising enzymes expression. In conclusion, the components of the GABAergic signalling system are relatively robust in the human hippocampus during ageing and between the sexes. However, there are some changes in GABAAR subunit expression between sexes and with ageing, which may greatly influence GABAergic inhibition and can lead to age- and sex specific disease susceptibility and progression.