Constitutive activation of the G-protein subunit Gαs within forebrain neurons causes PKA-dependent alterations in fear conditioning and cortical Arc mRNA expression

Kelly, M. P., Cheung, Y.-F., Favilla, C., Siegel, S. J., Kanes, S. J., Houslay, M. D. and Abel, T. (2008) Constitutive activation of the G-protein subunit Gαs within forebrain neurons causes PKA-dependent alterations in fear conditioning and cortical Arc mRNA expression. Learning and Memory, 15(2), pp. 75-83. (doi:10.1101/lm.723708)

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Publisher's URL: http://dx.doi.org/10.1101/lm.723708

Abstract

Memory formation requires cAMP signaling; thus, this cascade has been of great interest in the search for cognitive enhancers. Given that medications are administered long-term, we determined the effects of chronically increasing cAMP synthesis in the brain by expressing a constitutively active isoform of the G-protein subunit Gαs (Gαs*) in postnatal forebrain neurons of mice. Previously, we showed that G{alpha}s* mice exhibit increased adenylyl cyclase activity but decreased cAMP levels in cortex and hippocampus due to a PKA-dependent increase in total cAMP phosphodiesterase (PDE) activity. Here, we extend previous findings by determining if Gαs* mice show increased activity of specific PDE families that are regulated by PKA, if Gαs* mice show PKA-dependent deficits in fear memory, and if these memory deficits are associated with PKA-dependent alterations in neuronal activity as mapped by Arc mRNA expression. Consistent with previous findings, we show here that Gαs* mice exhibit a significant compensatory increase in cAMP PDE1 activity and a trend toward increased cAMP PDE4 activity. Further, inhibiting the presumably elevated PKA activity in Gαs* mice fully rescues short- and long-term memory deficits in a fear-conditioning task, while extending the training session from one to four CSUS pairings partially rescues these deficits. Mapping of Arc mRNA levels suggests these PKA-dependent memory deficits may be related to decreased neuronal activity specifically within the cortex. Gαs* mice show decreased Arc mRNA expression in CA1, orbital cortex, and cortical regions surrounding the hippocampus; however, only the deficits in cortical regions surrounding the hippocampus are PKA dependent. Our results imply that chronically stimulating targets upstream of cAMP may detrimentally affect cognition.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Houslay, Professor Miles
Authors: Kelly, M. P., Cheung, Y.-F., Favilla, C., Siegel, S. J., Kanes, S. J., Houslay, M. D., and Abel, T.
Subjects:Q Science > QP Physiology
College/School:College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Journal Name:Learning and Memory
Publisher:Cold Spring Harbor Laboratory Press
ISSN:1072-0502
ISSN (Online):1549-5485
Published Online:28 January 2008
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
438301Phosphodiesterase-4 isoforms - intracellular targeting, regulation and potential therapeutic targetsMiles HouslayMedical Research Council (MRC)G0600765Institute of Neuroscience and Psychology
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
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343641PDE4 cAMP phosphodiesterases - intracellular targeting, SH3 Domain Interaction & phosphorylation by stress kinasesMiles HouslayMedical Research Council (MRC)G8604010Institute of Neuroscience and Psychology
93971Sustainability and maturity in community-based housing organisationsKeith KintreaEconomic & Social Research Council (ESRC)L311253039Urban Studies