Age- and gender-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. GABA-A receptors are perhaps the most important aspect of the GABAergic signaling system in terms of diversity of function. Variation in function of different GABA-A receptors can be attributed to the range of subunits that form GABA-A receptors. Subunit composition changes over the lifetime and is implicated in not only normal aging, but also the pathology of several diseases. The hippocampus is one of the most important memory centers, belonging to the limbic system and playing an important role in the consolidation of information from short-term memory to long-term memory, and in spatial memory that enables navigation. Hippocampal function is impaired during aging and age-related disorders. We hypothesised that alteration in subunit composition would change the function of GABAergic channels, thereby affecting GABAergic inhibition in the hippocampus through aging. Furthermore, gender differences may also contribute to subunit diversity. This study was the first detailed analysis of the age and gender-specific changes of the GABA signalling components (synthesising enzymes, receptors and transporters) in the human hippocampus using Western Blotting, Immunohistochemistry (IHC) and confocal microscopy. The results show a significant increase in gamma-2 subunit expression in the dentate gyrus, CA1 and ECx with significantly greater expression in the old female than the old male group across all three regions. However, the rest of the GABA-A receptor subunits examined did not show significant differences between age and gender groups in any of the hippocampal regions examined. Additionally IHC showed a layer-specific change in gamma-2 expression, between the same old male and old female groups, with the males showing increased expression in the Stratum oriens. In conclusion, GABA-A receptor subunit composition changes with time and between genders and these changes likely influences GABA-A receptor function through healthy aging. The GABAergic inhibition within the DG, CA1 and ECx may all be impacted. Further understanding in this area will help with understanding of healthy aging and also the changes that occur in some pathological states along with potential avenues and targets for treatment.