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

Molecular psychiatry | Apr 24, 2009

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 Galphas was genetically linked to schizophrenia. Here we show that regulated overexpression of Galphas 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 Galphas 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 Galphas-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 Galphas 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.

Pubmed ID: 19030002 RIS Download

Mesh terms: Acetylcysteine | Acoustic Stimulation | Age Factors | Analysis of Variance | Animals | Animals, Newborn | Antipsychotic Agents | Behavior, Animal | Brain | Cognition Disorders | Conditioning (Psychology) | Cyclic AMP | Disease Models, Animal | Erythromycin | Exploratory Behavior | Fear | Female | GTP-Binding Protein alpha Subunits, Gs | Gene Expression Regulation, Developmental | Haloperidol | Male | Maze Learning | Mice | Mice, Inbred C57BL | Mice, Transgenic | Phosphodiesterase Inhibitors | Psychophysics | Reflex, Startle | Rolipram | Time Factors

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Associated grants

  • Agency: NIAAA NIH HHS, Id: R01 AA009000
  • Agency: NIMH NIH HHS, Id: T32 MH019112
  • Agency: NIGMS NIH HHS, Id: GM07517
  • Agency: NIA NIH HHS, Id: R01 AG18199
  • Agency: NIMH NIH HHS, Id: P50 MH064045
  • Agency: NIA NIH HHS, Id: R01 AG018199
  • Agency: NIMH NIH HHS, Id: R01 MH060244-02
  • Agency: NIMH NIH HHS, Id: K08 MH067091
  • Agency: NHLBI NIH HHS, Id: T32 HL007953
  • Agency: NIAAA NIH HHS, Id: AA09000
  • Agency: NHLBI NIH HHS, Id: T32 HL007953-01
  • Agency: NIMH NIH HHS, Id: K08 MH067091-01
  • Agency: NIMH NIH HHS, Id: R01 MH60244
  • Agency: NIAAA NIH HHS, Id: R01 AA009000-10
  • Agency: NIMH NIH HHS, Id: P50 MH 6404501
  • Agency: NIMH NIH HHS, Id: P50 MH064045-01
  • Agency: NIA NIH HHS, Id: R01 AG018199-01
  • Agency: NIGMS NIH HHS, Id: T32 GM007517
  • Agency: NHLBI NIH HHS, Id: T32 HL07953
  • Agency: NIMH NIH HHS, Id: R01 MH060244
  • Agency: NIMH NIH HHS, Id: T32 MH019112-09
  • Agency: NIGMS NIH HHS, Id: T32 GM007517-21

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