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Developmental etiology for neuroanatomical and cognitive deficits in mice overexpressing Gαs, a G-protein subunit genetically linked to schizophrenia

A Corrigendum to this article was published on 18 November 2009

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.

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Acknowledgements

We thank Dr Raquel Gur for helpful discussions, Dr Jean Richa for efforts in generating our transgenic mice and Jan Tokarczyk for technical assistance. We also acknowledge the following sources of funding: Tourettes Syndrome Association (MPK), NIMH T32 MH019112 (to MPK, R Gur, PI), Systems and Integrative Biology Training grant GM07517 (to CGV; M Nusbaum, PI), NIH T32 HL07953 (to CGV; AI Pack, PI), NIMH K08 MH067091 (SJK), NIAA AA09000 (GW), Merck, Whitehall and Packard Foundations as well as NIMH R01 MH60244, NIA R01 AG18199 and P50 MH 6404501 (Project 3 to TA; R Gur, Conte Center, PI). MPK and SJK are currently employed at Wyeth and AstraZeneca, respectively.

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Correspondence to M P Kelly.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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Kelly, M., Stein, J., Vecsey, C. et al. Developmental etiology for neuroanatomical and cognitive deficits in mice overexpressing Gαs, a G-protein subunit genetically linked to schizophrenia. Mol Psychiatry 14, 398–415 (2009). https://doi.org/10.1038/mp.2008.124

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