Involvement of 5HT1A receptor‐mediated inhibition of GSK3 beta in the antidepressant‐like phenotype of RGS‐insensitive mice

Abstract

We have shown that mice lacking Regulators of G Protein Signaling (RGS) activity at Gαi2 (Gαi2(G184S)) exhibit an antidepressant‐like phenotype with enhanced activity in response to SSRIs and 5HT1A agonists. Glycogen synthase kinase‐3β (GSK3β) is a constitutively active, pro‐apoptotic kinase that is inhibited by serotonin, SSRIs and 5HT1 receptor agonists via phosphorylation at Ser‐9. Therefore, we tested whether GSK3β activity was altered in RGS‐insensitive Gαi2(G184S) mice. Heterozygous (GS/+) and homozygous (GS/GS) Gαi2(G184S) animals showed increased basal GSK3β phosphorylation at Ser‐9 in the cortex and hippocampus. WAY 100635, a 5HT1A receptor antagonist, caused a reduction of phospho‐GSK3β in the cortex and hippocampus of both GS/+ and GS/GS but not wild‐type animals. Behaviorally, treatment of Gαi2(G184S) mice with the same dose of WAY 100635 reversed the antidepressant‐like phenotype in the tail suspension test, an established rodent model of antidepressant‐like behavior. These data demonstrate that enhancing Gαi2 activity by the removal of RGS protein regulation at Gαi2 results in an antidepressant‐like phenotype that is manifest both biochemically and behaviorally and is reversed by 5HT1A receptor blockade. Supported by DA04087, GM39561, T32 DA007268, the Bower, Bennet, & Bennet Endowed Chair Research Award, and the AACP New Investigator Program Award.