Changes in GABAA Receptor Subunit Distribution during Brain Maturation and Aging

Gamma-aminobutyric acid type A (GABAA) receptors are the most important inhibitory receptors in the central nervous system playing a pivotal role in the regulation of brain excitability. The pentameric receptor is usually composed of different alpha, beta, and gamma subunits which modulate the pharmacology of the receptor. Up to now, a diversity of 20 different subunits is known allowing a multitude of adaptive changes under physiological and pathophysiological conditions. In this study, we investigated the expression of five major GABAA receptors subunits (alpha1, alpha2, alpha3, alpha5, gamma2) during brain maturation and ageing in the rat brain. Wistar rats were perfused at day 10, 30, 90, 180, 360, and 540 after birth and immunohistochemistry was performed using antibodies against alpha1, alpha2, alpha3, alpha5, and gamma2 subunits of the GABAA receptor. Morphological and semi-quantitative evaluation of regional optical densities revealed that each of these subunits exhibited age-dependent changes in its regional distribution. During the first postnatal days, subunits alpha2 and alpha5 were abundantly expressed in the cortex whereas only marginal amounts of alpha1 and gamma2 subunits were found in this brain region. In the following weeks the expression of subunits alpha1, alpha2, alpha3, and gamma2 then increased in the cortex and subunit alpha5 in contrast showed a decrease in optical density. After an age of 3 months a continuous down-regulation of subunits alpha3, alpha5, and gamma2 was observed in the cortex whereas subunits alpha1 and alpha2 remained stable on a high expression level. In the hippocampal formation differential temporal alterations in GABAA receptor expression occurred. The present study demonstrates that GABAA receptors show specific changes in subunit composition during brain maturation and ageing. These findings probably contribute to a better understanding of age-related changes in excitability and might further explain the distinct pharmacological effects of different GABAergic drugs in young and elderly patients.