Journal article
Developmental etiology for neuroanatomical and cognitive deficits in mice overexpressing Gαs, a G-protein subunit genetically linked to schizophrenia
Molecular psychiatry, Vol.14(4), pp.398-415
04/2009
DOI: 10.1038/mp.2008.124
PMCID: PMC3312743
PMID: 19030002
Abstract
Schizophrenia is a widespread psychiatric disorder, affecting 1% of people. Despite this high prevalence, schizophrenia is not well treated because of its enigmatic developmental origin. We explore here the developmental etiology of endophenotypes associated with schizophrenia using a regulated transgenic approach in mice. Recently, a polymorphism that increases mRNA levels of the G-protein subunit Gαs was genetically linked to schizophrenia. Here we show that regulated overexpression of Gαs mRNA in forebrain neurons of mice is sufficient to cause a number of schizophrenia-related phenotypes, as measured in adult mice, including sensorimotor gating deficits (prepulse inhibition of acoustic startle, PPI) that are reversed by haloperidol or the phosphodiesterase inhibitor rolipram, psychomotor agitation (hyperlocomotion), hippocampus-dependent learning and memory retrieval impairments (hidden water maze, contextual fear conditioning), and enlarged ventricles. Interestingly, overexpression of Gαs during development plays a significant role in some (PPI, spatial learning and memory and neuroanatomical deficits) but not all of these adulthood phenotypes. Pharmacological and biochemical studies suggest the Gαs-induced behavioral deficits correlate with compensatory decreases in hippocampal and cortical cyclic AMP (cAMP) levels. These decreases in cAMP may lead to reduced activation of the guanine exchange factor Epac (also known as RapGEF 3/4) as stimulation of Epac with the select agonist 8-pCPT-2′-
O
-Me-cAMP increases PPI and improves memory in C57BL/6J mice. Thus, we suggest that the developmental impact of a given biochemical insult, such as increased Gαs expression, is phenotype specific and that Epac may prove to be a novel therapeutic target for the treatment of both developmentally regulated and non-developmentally regulated symptoms associated with schizophrenia.
Details
- Title: Subtitle
- Developmental etiology for neuroanatomical and cognitive deficits in mice overexpressing Gαs, a G-protein subunit genetically linked to schizophrenia
- Creators
- M P Kelly - Department of Biology, University of Pennsylvania, Monmouth Junction, NJ, USAT Abel - Department of Biology, University of Pennsylvania, Monmouth Junction, NJ, USAJ M Stein - Department of Biology, University of Pennsylvania, Monmouth Junction, NJ, USAC G Vecsey - Neuroscience Graduate Group, University of Pennsylvania, Monmouth Junction, NJ, USAC Favilla - Department of Biology, University of Pennsylvania, Monmouth Junction, NJ, USAX Yang - Department of Endocrinology and Metabolism, Johns Hopkins University, Monmouth Junction, NJ, USAS F Bizily - Department of Biology, University of Pennsylvania, Monmouth Junction, NJ, USAM F Esposito - Department of Biology, University of Pennsylvania, Monmouth Junction, NJ, USAG Wand - Department of Endocrinology and Metabolism, Johns Hopkins University, Monmouth Junction, NJ, USAS J Kanes - Department of Psychiatry, University of Pennsylvania, Monmouth Junction, NJ, USA
- Resource Type
- Journal article
- Publication Details
- Molecular psychiatry, Vol.14(4), pp.398-415
- DOI
- 10.1038/mp.2008.124
- PMID
- 19030002
- PMCID
- PMC3312743
- NLM abbreviation
- Mol Psychiatry
- ISSN
- 1359-4184
- eISSN
- 1476-5578
- Grant note
- T32 HL007953-01 || HL / National Heart, Lung, and Blood Institute : NHLBI T32 MH019112-09 || MH / National Institute of Mental Health : NIMH K08 MH067091-01 || MH / National Institute of Mental Health : NIMH P50 MH064045-01 || MH / National Institute of Mental Health : NIMH R01 AG018199-01 || AG / National Institute on Aging : NIA
- Language
- English
- Date published
- 04/2009
- Academic Unit
- Molecular Physiology and Biophysics; Psychiatry; Psychological and Brain Sciences; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Biochemistry and Molecular Biology
- Record Identifier
- 9984065830002771
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