Ethanol-induced GABAA receptor alpha4 subunit plasticity involves phosphorylation and neuroactive steroids

GABAA receptors containing alpha4 subunits are widely implicated in acute ethanol sensitivity, and their spatial and temporal regulation prominently contributes to ethanol-induced neuroplasticity in hippocampus and cortex. However, it is unknown if alpha4-containing GABAA receptors in the thalamus, an area of high alpha4 expression, display similar regulatory patterns following ethanol administration, and if so, by which molecular mechanisms. In the current study, thalamic GABAA receptor alpha4 subunit levels were increased following a 6-week-, but not a 2-week chronic ethanol diet. Following acute high-dose ethanol administration, thalamic GABAA receptor alpha4 subunit levels were regulated in a temporal fashion, as a decrease was observed at 2 h followed by a delayed transient increase. PKCgamma and PKCdelta levels paralleled alpha4 temporal expression patterns following ethanol exposure. Initial decreases in alpha4 subunit expression were associated with reduced serine phosphorylation. Delayed increases in expression were not associated with a change in phosphorylation state, but were prevented by inhibiting neuroactive steroid production with the 5alpha-reductase inhibitor finasteride. Overall, these studies indicate that thalamicGABAA receptor alpha4 subunit expression following acute and chronic ethanol administration exhibits similar regulatory patterns as other regions and that transient expression patterns following acute exposure in vivo are likely dependent on both subunit phosphorylation state and neuroactive steroids.