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 > School of Psychology & Neuroscience |
| Journal Name: | Learning and Memory |
| Publisher: | Cold Spring Harbor Laboratory Press |
| ISSN: | 1072-0502 |
| ISSN (Online): | 1549-5485 |
| Published Online: | 28 January 2008 |
| Related URLs: |
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