The pathological consequences of ethanol dependence that involve adaptations of GABA-A receptors include heightened CNS excitability, seizures, tremor, anxiety, and cognitive deficits. We have shown that the GABA-A receptor adaptations involved are dependent upon PKC gamma and moderated by protein kinase A (PKA). The goal of this project is to systematically delineate the protective role of PKA in ethanol dependence pethology mediated by GABA-A receptors and to determine the cellular localization of GABA-A receptor adaptations in cortical circuits.
The first aim will examine PKA regulation of GABA-A receptor trafficking and synaptic function in cultured cortical neurons. We will investigate whether pharmacological activation of PKA or inhibition using siRNA alters ethanol-induced internalization of GABA-A al receptors and increased surface expression of a4 receptors.
The second aim will determine if PKA modulates the ethanol dependence phenotypes of GABA-A receptor trafficking, increased seizure susceptibility or withdrawal-induced anxiety-like behavior in vivo. PKARlip mutant mice (PKARlip-/-) will be utilized since they exhibit complete loss of PKARlip expression and 50% loss of the A kinase anchoring protein (AKAP150), producing phenotypes with GABA-A receptor dysfunction. We will examine receptor surface expression, seizure thresholds and withdrawal-induced anxiety-like behavior.
The final aim will identify the cortical neurons that exhibit ethanol-induced alterations in the trafficking and function of GABA-A al and a4 receptors and test their sensitivity to PKA activity. We plan to determine the effects of chronic ethanol exposure on GABA-A al and a4 receptors using specific markers for GABAergic interneurons (parvalbumin) or pyramidal projection neurons (Cam Kinase II) via dual label confocal microscopy. Electrophysiological responses will be determined by voltage clamp recording within slices and the effects of PKA activation will be determined in these cells. These studies will delineate the role of PKA in GABA-A receptor adaptations associated with ethanol dependence and identify intracortical pathology that results from GABA-A receptor adaptations to chronic ethanol exposure. This work will elucidate specific targets for reversal of ethanol dependence pathopathology.
The mechanisms that underiie ethanol dependence pathogenesis involve alterations in the trafficking of GABA-A receptors in brain. We've discovered that protein kinases mediate this effect of ethanol and this has lead to a strategy to prevent or ameliorate these adaptations. The proposed studies will investigate protein kinase inhibition of ethanol dependence pathogenesis both in vitro and in vivo. This work may lead to new therapeutics for alcoholism.
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