Temporal Regulation of GABA(A) Receptor Subunit Expression: Role in Synaptic and Extrasynaptic Communication in the Suprachiasmatic Nucleus

Recent molecular studies suggest that the expression levels of δ and γ2 GABA(A) receptor (GABA(A)R) subunits regulate the balance between synaptic and extrasynaptic GABA neurotransmission in multiple brain regions. We investigated the expression of GABA(A)δ and GABA(A)γ2 and the functional significance of a change in balance between these subunits in a robust local GABA network contained within the suprachiasmatic nucleus of the hypothalamus (SCN). Muscimol, which can activate both synaptic and extrasynaptic GABA(A)Rs, injected into the SCN during the day phase advanced the circadian pacemaker, whereas injection of the extrasynaptic GABA(A) superagonist 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP) had no effect on circadian phase. In contrast, injection of either THIP or muscimol during the night was sufficient to block the phase shifting effects of light. Gene expression analysis of the whole SCN revealed different temporal patterns in GABA(A)δ and GABA(A)γ2 mRNA expression. When examined across all subregions of the SCN, quantitative immunohistochemical analysis found no significant variations in GABA(A)δ protein immunoreactivity (IR) but did find significant variations in GABA(A)γ2 protein-IR in hamsters housed in either LD cycles or in constant darkness. Remarkably, significant interactions in the ratio of GABA(A)δ:GABA(A)γ2 subunits between lighting condition and circadian phase occurred only within one highly discrete anatomical area of the SCN; a region that functions as the input for lighting information from the retina. Taken together, these data support the hypothesis that the balance between synaptic and extrasynaptic GABA(A)Rs determines the functional response to GABA, and that this balance is differentially regulated in a region-specific manner.