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

Learn Mem. 2008 Jan 28;15(2):75-83. doi: 10.1101/lm.723708. Print 2008 Feb.

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 Galphas (Galphas*) in postnatal forebrain neurons of mice. Previously, we showed that Galphas* 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 Galphas* mice show increased activity of specific PDE families that are regulated by PKA, if Galphas* 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 Galphas* 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 Galphas* 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. Galphas* 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological
  • Animals
  • Cerebral Cortex / metabolism*
  • Conditioning, Psychological / physiology*
  • Cues
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic AMP-Dependent Protein Kinases / physiology*
  • Cytoskeletal Proteins / genetics*
  • Fear / physiology*
  • GTP-Binding Protein alpha Subunits, Gs / physiology*
  • Hydrolysis
  • Memory
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nerve Tissue Proteins / genetics*
  • Neurons / metabolism
  • Phosphoric Diester Hydrolases / metabolism
  • Practice, Psychological
  • Prosencephalon / metabolism*
  • RNA, Messenger / metabolism*
  • Tissue Distribution

Substances

  • Cytoskeletal Proteins
  • Nerve Tissue Proteins
  • RNA, Messenger
  • activity regulated cytoskeletal-associated protein
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Phosphoric Diester Hydrolases
  • GTP-Binding Protein alpha Subunits, Gs