Constitutive Activation of the G-Protein Subunit G[alpha]s within Forebrain Neurons Causes PKA-Dependent Alterations in Fear Conditioning and Cortical "Arc" mRNA Expression

Autor/inn/en	Kelly, Michele P.; Cheung, York-Fong; Favilla, Christopher; Siegel, Steven J.; Kanes, Stephen J.; Houslay, Miles D.; Abel, Ted
Titel	Constitutive Activation of the G-Protein Subunit G[alpha]s within Forebrain Neurons Causes PKA-Dependent Alterations in Fear Conditioning and Cortical "Arc" mRNA Expression
Quelle	In: Learning & Memory, 15 (2008) 2, S.75-83 (9 Seiten) PDF als Volltext Verfügbarkeit
Sprache	englisch
Dokumenttyp	gedruckt; online; Zeitschriftenaufsatz
ISSN	1072-0502
DOI	10.1101/lm.723708
Schlagwörter	Animals; Conditioning; Long Term Memory; Fear; Short Term Memory; Stimulation + Suchen Sie Ihr Suchwort? Animal; Tier; Tiere; Langzeitgedächtnis; Furcht; Kurzzeitgedächtnis
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 G[alpha]s (G[alpha]s) 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 G[alpha]s* mice show increased activity of specific PDE families that are regulated by PKA, if G[alpha]s* 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 G[alpha]s* 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 G[alpha]s* 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. G[alpha]s* 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. (Author).
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Erfasst von	ERIC (Education Resources Information Center), Washington, DC
Update	2017/4/10