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

doi:10.1038/sj.npp.1301099

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Constitutive Activation of Gαs within Forebrain Neurons Causes Deficits in Sensorimotor Gating Because of PKA-Dependent Decreases in cAMP

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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, …

Neuropsychopharmacology (New York, N.Y.), Vol.32(3), pp.577-588

03/2007

DOI: 10.1038/sj.npp.1301099

PMCID: PMC3303872

PMID: 16738544

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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.

GNAS

schizophrenia

Tourette’s syndrome

genetic mouse model

preattentional processing

Gs alpha

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Title: Subtitle: Constitutive Activation of Gαs within Forebrain Neurons Causes Deficits in Sensorimotor Gating Because of PKA-Dependent Decreases in cAMP
Creators: Michele P Kelly - Department of Biology, University of Pennsylvania, Philadelphia, PA, USA
Carolina Isiegas - Department of Biology, University of Pennsylvania, Philadelphia, PA, USA
York-Fong Cheung - Division of Biochemistry and Molecular Biology, University of Glasgow, Glasgow, UK
Jan Tokarczyk - Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA
Xioaju Yang - Department of Endocrinology and Metabolism, Johns Hopkins University, Baltimore, MD, USA
Michael F Esposito - Department of Biology, University of Pennsylvania, Philadelphia, PA, USA
David A Rapoport - Department of Biology, University of Pennsylvania, Philadelphia, PA, USA
Sara A Fabian - Department of Biology, University of Pennsylvania, Philadelphia, PA, USA
Steven J Siegel - Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA
Gary Wand - Department of Endocrinology and Metabolism, Johns Hopkins University, Baltimore, MD, USA
Miles D Houslay - Division of Biochemistry and Molecular Biology, University of Glasgow, Glasgow, UK
Stephen J Kanes - Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA
Ted Abel - Department of Biology, University of Pennsylvania, Philadelphia, PA, USA
Resource Type: Journal article
Publication Details: Neuropsychopharmacology (New York, N.Y.), Vol.32(3), pp.577-588
DOI: 10.1038/sj.npp.1301099
PMID: 16738544
PMCID: PMC3303872
ISSN: 0893-133X
eISSN: 1740-634X
Grant note: T32 MH019112-09 || MH / National Institute of Mental Health : NIMH R01 MH060244-01A1 || MH / National Institute of Mental Health : NIMH P50 MH064045-01 || MH / National Institute of Mental Health : NIMH
Language: English
Date published: 03/2007
Academic Unit: Molecular Physiology and Biophysics; Psychiatry; Psychological and Brain Sciences; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Biochemistry and Molecular Biology
Record Identifier: 9984065732102771

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