Constitutive activation of G alpha s within forebrain neurons causes deficits in sensorimotor gating because of PKA-dependent decreases in cAMP

Kelly, M. P. et al. (2007) Constitutive activation of G alpha s within forebrain neurons causes deficits in sensorimotor gating because of PKA-dependent decreases in cAMP. Neuropsychopharmacology, 32, pp. 577-588. (doi:10.1038/sj.npp.1301099)

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Publisher's URL: http://dx.doi.org/10.1038/sj.npp.1301099

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 Galphas (Galphas*) 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 Galphas* 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 Galphas* increases cAMP levels in the striatum. Suprisingly, however, Galphas* 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 Galphas* on PPI because Rp-cAMPS decreases PPI in C57BL/6J mice. Furthermore, the antipsychotic haloperidol increases both PPI and cAMP levels specifically in Galphas* mice and the cPDE inhibitor rolipram also rescues PPI deficits of Galphas* mice. Finally, to block potentially the pathway that leads to cPDE upregulation in Galphas* 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 Galphas*. We conclude that expression of Galphas* 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Houslay, Professor Miles
Authors: Kelly, M. P., Isiegas, C., Cheung, Y.-F., Tokarczyk, J., Yang, X., Esposito, M. F., Rapoport, D. A., Fabian, S. A., Siegel, S. J., Wand, G., Houslay, M. D., Kanes, S. J., and Abel, T.
College/School:College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Journal Name:Neuropsychopharmacology
Publisher:Nature Publishing Group
ISSN:0893-133X
ISSN (Online):1740-634X
Published Online:31 May 2006
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
208361PDE4 cAMP phosphodiesterses: intracellular targeting, SH3 domain interaction and phosphorylation by stress kinasesMiles HouslayMedical Research Council (MRC)G8604010Institute of Neuroscience and Psychology
294081PDE4 Cyclic AMP phosphodiesterasesMiles HouslayMedical Research Council (MRC)G8604010Institute of Neuroscience and Psychology
30691Molecular interaction between receptor signal transduction systems involving guanine nucleotide regulatory proteinsMiles HouslayMedical Research Council (MRC)PG8604010Institute of Neuroscience and Psychology
343641PDE4 cAMP phosphodiesterases - intracellular targeting, SH3 Domain Interaction & phosphorylation by stress kinasesMiles HouslayMedical Research Council (MRC)G8604010Institute of Neuroscience and Psychology
97371Programme Grant (PG 8604010) Supplementation (Equipment). Molecular interaction between receptor transduction systems involving guanine nuclMiles HouslayMedical Research Council (MRC)G8604010Institute of Neuroscience and Psychology