Modulation by the GABA(B) receptor siRNA of ethanol-mediated PKA-α, CaMKII, and p-CREB intracellular signaling in prenatal rat hippocampal neurons.

Fetal alcohol syndrome (FAS) is a developmental neuropathology resulting from in utero exposure to ethanol; many of ethanol's effects are likely to be mediated by the neurotransmitter γ-aminobutyric acid (GABA). We studied modulation of the neurotransmitter receptor GABA(B)R and its capacity for intracellular signal transduction under conditions of ethanol treatment (ET) and RNA interference to investigate a potential role for GABA signaling in FAS. ET increased GABA(B1)R protein levels, but decreased protein kinase A-α (PKA-α), calcium/calmodulin-dependent protein kinase II (CaMKII) and phosphorylation of cAMP-response element binding protein (p-CREB), in cultured hippocampal neurons harvested at gestation day 17.5. To elucidate GABA(B1)R response to ethanol, we observed the effects of a GABA(B)R agonist and antagonist in pharmacotherapy for ethanol abuse. Baclofen increased GABA(B)R, CaMKII and p-CREB levels, whereas phaclofen decreased GABA(B)R, CaMKII and p-CREB levels except PKA-α. Furthermore, when GABA(B1)R was knocked down by siRNA treatment, CaMKII and p-CREB levels were reduced upon ET. We speculate that stimulation of GABA(B1)R activity by ET can modulate CaMKII and p-CREB signaling to detrimental effect on fetal brain development.