Regulator of G protein signaling 6 promotes anxiety and depression by attenuating serotonin‐mediated activation of the 5‐HT1A receptor‐adenylyl cyclase axis (803.12)

Abstract

The limited efficacy, delayed onset of action, and side effects restrict the clinical utility of selective serotonin (5‐HT) reuptake inhibitors (SSRIs), which remain first line therapies in the treatment of mood disorders. Regulator of G protein Signaling (RGS) proteins have been implicated as key regulators of 5‐HT1ARs, believed to underlie the beneficial effects of SSRIs, but the identity of the specific RGS protein involved remains unknown. Here, we identify RGS6 as the critical negative regulator of 5‐HT1AR‐dependent anxiolytic and antidepressant actions. RGS6‐/‐ mice exhibit spontaneous anxiolytic and antidepressant behavior, a phenotype reversible by 5‐HT1AR blockade. Effects of the SSRI fluvoxamine and 5‐HT1AR agonist 8‐OH‐DPAT were also potentiated in RGS6+/‐ mice. The phenotype of RGS6‐/‐ mice was associated with decreased phospho‐CREB and reduced PKA activity implicating enhanced Gαi‐dependent adenylyl cyclase (AC) inhibition as a causative factor in RGS6‐/‐ animal behavior. In fact, direct activation of AC with forskolin reversed the antidepressant phenotype of RGS6‐/‐ mice. Thus, by inhibiting 5‐HT activation of postsynaptic 5‐HT1ARs, RGS6 exerts powerful anxiogenic and pro‐depressant actions indicating that RGS6 inhibition may represent a viable means to enhance the efficacy of serotonergic drugs through selective potentiation of 5‐HT1AR‐mediated inhibition of AC.Grant Funding Source: Supported by NIH CA161882, 1R01MH085724‐01, 5 R01 HL113863‐01