Plasticity of the α4βδ GABAA receptor

Abstract

The GABAR [GABAA (γ-aminobutyric acid type A) receptor], which mediates most inhibition in the brain, is regulated homoeostatically to maintain an optimal level of neuronal excitability. In particular, the α4βδ subtype of the GABAR plays a pivotal role in this regulation. This receptor, which is expressed extrasynaptically on the dendrites, normally has low expression in the brain, but displays a remarkable degree of plasticity. It can also be a sensitive target for endogenous neurosteroids such as THP (3α-hydroxy-5[α]β-pregnan-20-one (allo-pregnanolone); a neurosteroid and positive modulator of the GABAR), which is released during stress, although the effect of the steroid is polarity-dependent, such that it increases inward current, but decreases outward current, at α4β2δ GABAR. Expression of α4β2δ GABAR in CA1 hippocampus is also tightly regulated by fluctuating levels of neurosteroids, as seen at the onset of puberty. Declining levels of inhibition resulting from the decrease in THP at puberty are compensated for by an increase in α4βδ GABAR along the apical dendrites of CA1 hippocampal pyramidal cells, which reduces neuronal excitability by decreasing the input resistance. However, excessive decrease of neuronal function is averted when THP levels rise, as would occur during stress, because this steroid decreases the outward GABAergic tonic current via inhibition of α4β2δ GABAR, thereby restoring measures of neuronal excitability to pre-pubertal levels. Thus the homoeostatic regulation of α4βδ GABAR expression plays an important role in maintaining ambient levels of neuronal excitability at puberty.