GABAA receptor plasticity in the hippocampus of socially isolated C57BL/6J mice exposed to voluntary ethanol consumption

Social isolation (SI) is a model of prolonged mild stress that has been shown to be associated, in the rat, with marked behavioral alterations, a decrease in brain and plasma concentrations of neuroactive steroids, and an abnormal response to acute stressful stimuli as well as an increased neurosteroidogenic effect induced by the acute administration of ethanol (EtOH). We here used social isolation in the C57BL/6J mouse strain to investigate the effect EtOH in the free-choice drinking paradigm on gene expression and function of GABAA receptor (GABAAR) in the hippocampus. Socially isolated (SI) and group-housed (GH) mice were exposed for 6 weeks to the two-bottle choice (EtOH vs. water). Both groups of animals were given, during the whole period of isolation free access to EtOH for 2 hour in their home cage, beginning at 0.5 hour prior the start of the dark cycle. Mice from both experimental groups were individually housed for the 2-h procedure. Specific GABAAR subunits expression were measured by RNase protection assay and immunohistochemistry. GABAAR function was evaluated by conventional whole-cell patch clamp recording in brain slices. We found a significant increase in the abundance of both a4 and d subunits of the GABAAR in the hippocampus of SI mice (+20 and 26% respectively p < 0.001) compared to GH animals. On the contrary the abundance of the a1 subunit mRNA was unchanged in SI mice as compared to GH mice. Voluntary EtOH drinking resulted in a marked increase (89%, p < 0.01) in d subunit mRNA levels in GH mice, whereas in SI animals, it completely abolished the increase in a4 subunit mRNA but did not alter that of the d subunit with respect to the SI mice. Parallel changes in a4 and d subunit peptides were observed by immunohistochemistry. Patch clamp recording in dentate gyrus granule cells obtained from SI mice revealed a greater enhancement of tonic currents induced by THIP compared to that in GH animals. Voluntary EtOH consumption reduced the increase in tonic current associated with social isolation. These results suggest that voluntary EtOH drinking in SI mice has a selective influence on a4 subunit since blocks its enhanced expression but fails to alter the up-regulation of d subunit