1. ¹Department of Biology, University of Pennsylvania, Philadelphia, PA, USA
2. ²Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA
3. ³Division of Biochemistry and Molecular Biology, University of Glasgow, Glasgow, UK
4. ⁴Department of Endocrinology and Metabolism, Johns Hopkins University, Baltimore, MD, USA

Correspondence: Dr MP Kelly, Department of Biology, University of Pennsylvania, 319 Leidy Labs, 3740 Hamilton Walk, Philadelphia, PA 19104, USA, Tel: +1 215 898 3155; Fax: +1 215 898 8780, E-mail: mpkelly@bbl.med.upenn.edu

Received 24 October 2005; Revised 5 April 2006; Accepted 5 April 2006; Published online 31 May 2006.

Abstract

Sensorimotor gating, the ability to automatically filter sensory information, is deficient in a number of psychiatric disorders, yet little is known of the biochemical mechanisms underlying this critical neural process. Previously, we reported that mice expressing a constitutively active isoform of the G-protein subunit Gs (Gs^*) within forebrain neurons exhibit decreased gating, as measured by prepulse inhibition of acoustic startle (PPI). Here, to elucidate the biochemistry regulating sensorimotor gating and to identify novel therapeutic targets, we test the hypothesis that Gs^* causes PPI deficits via brain region-specific changes in cyclic AMP (cAMP) signaling. As predicted from its ability to stimulate adenylyl cyclase, we find here that Gs^* increases cAMP levels in the striatum. Suprisingly, however, Gs^* mice exhibit reduced cAMP levels in the cortex and hippocampus because of increased cAMP phosphodiesterase (cPDE) activity. It is this decrease in cAMP that appears to mediate the effect of Gs^* on PPI because Rp-cAMPS decreases PPI in C57BL/6J mice. Furthermore, the antipsychotic haloperidol increases both PPI and cAMP levels specifically in Gs^* mice and the cPDE inhibitor rolipram also rescues PPI deficits of Gs^* mice. Finally, to block potentially the pathway that leads to cPDE upregulation in Gs^* mice, we coexpressed the R(AB) transgene (a dominant-negative regulatory subunit of protein kinase A (PKA)), which fully rescues the reductions in PPI and cAMP caused by Gs^*. We conclude that expression of Gs^* within forebrain neurons causes PPI deficits because of a PKA-dependent decrease in cAMP and suggest that cAMP PDE inhibitors may exhibit antipsychotic-like therapeutic effects.