Altered GABAA receptor expression and seizure threshold following acute ethanol challenge in mice lacking the RIIβ subunit of PKA.

Abstract

Ethanol causes pathological changes in GABAA receptor trafficking and function. These changes are mediated in part by ethanol activation of protein kinase A (PKA). The current study investigated the expression of the GABAA α1 and α4 subunits and the kinase anchoring protein AKAP150, as well as bicuculline-induced seizure threshold, at baseline and following acute injection of ethanol (3.5 g/kg IP) in a mouse line lacking the regulatory RIIβ subunit of PKA. Whole cerebral cortices were harvested at baseline, 1 h, or 46 h following injection of ethanol or saline and subjected to fractionation and western blot analysis. Knockout (RIIβ-/-) mice had similar baseline levels of PKA RIIα and GABAA α1 and α4 subunits compared to wild type (RIIβ+/+) littermates, but had deficits in AKAP150. GABAA α1 subunit levels were decreased in the P2 fraction of RIIβ-/-, but not RIIβ+/+, mice following 1 h ethanol, an effect that was driven by decreased α1 expression in the synaptic fraction. GABAA α4 subunits in the P2 fraction were not affected by 1 h ethanol; however, synaptic α4 subunit expression was increased in RIIβ+/+, but not RIIβ-/- mice, while extrasynaptic α4 and δ subunit expression were decreased in RIIβ-/-, but not RIIβ+/+ mice. Finally, RIIβ knockout was protective against bicuculline-induced seizure susceptibility. Overall, the results suggest that PKA has differential roles in regulating GABAA receptor subunits. PKA may protect against ethanol-induced deficits in synaptic α1 and extrasynaptic α4 receptors, but may facilitate the increase of synaptic α4 receptors.

• Authors: Stephen L Carlson, Todd K O'Buckley, Rhiannon Thomas, Todd E Thiele, A Leslie Morrow
• Journal: Neurochemical research (Neurochem Res) Vol. 39 Issue 6 Pg. 1079-87 (Jun 2014) ISSN: 1573-6903 [Electronic] United States
• PMID: 24104609 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit
• Receptors, GABA-A
• Ethanol

Topics

• Animals
• Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit (deficiency)
• Ethanol (administration & dosage)
• Gene Expression Regulation
• Mice
• Mice, 129 Strain
• Mice, Inbred C57BL
• Mice, Knockout
• Receptors, GABA-A (biosynthesis)
• Seizures (chemically induced, metabolism)