Journal article
Constitutive activation of the G-protein subunit Gαs within forebrain neurons causes PKA-dependent alterations in fear conditioning and cortical Arc mRNA expression
Learning & memory (Cold Spring Harbor, N.Y.), Vol.15(2), pp.75-83
02/2008
DOI: 10.1101/lm.723708
PMCID: PMC2216679
PMID: 18230676
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 Gαs* 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 CS–US 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.
Details
- Title: Subtitle
- Constitutive activation of the G-protein subunit Gαs within forebrain neurons causes PKA-dependent alterations in fear conditioning and cortical Arc mRNA expression
- Creators
- Michele P Kelly - Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USAYork-Fong Cheung - Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, United KingdomChristopher Favilla - Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USASteven J Siegel - Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USAStephen J Kanes - Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USAMiles D Houslay - Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, United KingdomTed Abel - Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Resource Type
- Journal article
- Publication Details
- Learning & memory (Cold Spring Harbor, N.Y.), Vol.15(2), pp.75-83
- Publisher
- Cold Spring Harbor Laboratory Press
- DOI
- 10.1101/lm.723708
- PMID
- 18230676
- PMCID
- PMC2216679
- ISSN
- 1072-0502
- eISSN
- 1549-5485
- Alternative title
- Gαs causes PKA-dependent deficits in memory
- Language
- English
- Date published
- 02/2008
- Academic Unit
- Molecular Physiology and Biophysics; Psychiatry; Psychological and Brain Sciences; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Biochemistry and Molecular Biology
- Record Identifier
- 9984065829402771
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