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

Michele P. Kelly, Carolina Isiegas, York Fong Cheung, Jan Tokarczyk, Xioaju Yang, Michael F. Esposito, David A. Rapoport, Sara A. Fabian, Steven J. Siegel, Gary Wand, Miles D. Houslay, Stephen J. Kanes, Ted Abel

Research output: Contribution to journalArticle

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

Original languageEnglish (US)
Pages (from-to)577-588
Number of pages12
JournalNeuropsychopharmacology
Volume32
Issue number3
DOIs
StatePublished - Mar 1 2007

Keywords

  • GNAS
  • Genetic mouse model
  • Gs alpha
  • Preattentional processing
  • Schizophrenia
  • Tourette's syndrome

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

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    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., & Abel, T. (2007). Constitutive activation of Gαs within forebrain neurons causes deficits in sensorimotor gating because of PKA-dependent decreases in cAMP. Neuropsychopharmacology, 32(3), 577-588. https://doi.org/10.1038/sj.npp.1301099