title: Chronic Galphas signaling in the striatum increases anxiety-related behaviors independent of developmental effects.
abstract: Current research in the field of anxiety disorders is largely receptor-centric, leaving intracellular pathways largely unexplored. Galphas, the G-protein which stimulates adenylyl cyclase and L-type voltage-gated calcium channels, may be one intracellular molecule regulating anxiety-related behaviors as increased efficacy of Galphas signaling has been noted in patient populations that suffer from anxiety. We report here anxiety-related behaviors in two lines of transgenic mice expressing a constitutively active isoform of Galphas (or Galphas*). The first line expressed Galphas* throughout postnatal forebrain neurons, while the second line of mice conditionally expressed Galphas* selectively in the striatum (Galphas*(str) mice). In the open field, both lines of mice showed a significant preference for the periphery suggesting that expression of Galphas* in the striatum alone was sufficient to produce an anxiogenic phenotype. In the light/dark box, Galphas*(str) mice exhibited longer latencies to enter the light and spent significantly less time in the lit compartment. Similarly, Galphas*(str) mice showed longer latencies to enter the open quadrants and spent less time in the open quadrants of the elevated zero maze. Interestingly, these anxiety-related phenotypes were largely unrelated to developmental effects as mice expressing the Galphas*(str) transgene during development, but not at testing, were normal on most measures. These observations show that chronic Galphas signaling in the striatum is sufficient to trigger anxiety-related behaviors largely independent of developmental effects and suggest the cAMP pathway or L-type voltage-gated calcium channels may be viable targets for future pharmacological intervention in the treatment of anxiety disorders.
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Favilla
authors.forename: Ted
authors.initials: T
authors.lastname: Abel
authors.forename: Michele P
authors.initials: MP
authors.lastname: Kelly
mesh_terms: D000818:Animals; D001007:Anxiety / Q000235:genetics* / Q000378:metabolism; D001522:Behavior, Animal; D003342:Corpus Striatum / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D016548:Prosencephalon / Q000378:metabolism; D015290:Second Messenger Systems / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics*; D013037:Spatial Behavior
chemical_list: D000242:Cyclic AMP; D019205:GTP-Binding Protein alpha Subunits, Gs