Schizophrenia risk gene CAV1 is both pro-psychotic and required for atypical antipsychotic drug actions in vivo

J. A. Allen, P. N. Yadav, V. Setola, M. Farrell, B. L. Roth

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Caveolin-1 (Cav-1) is a scaffolding protein important for regulating receptor signaling cascades by partitioning signaling molecules into membrane microdomains. Disruption of the CAV1 gene has recently been identified as a rare structural variant associated with schizophrenia. Although Cav-1 knockout (KO) mice displayed no baseline behavioral disruptions, Cav-1 KO mice, similar to schizophrenic individuals, exhibited increased sensitivity to the psychotomimetic N-methyl-D-aspartate receptor antagonist phencyclidine (PCP). Thus, PCP disruption of prepulse inhibition (PPI) and PCP-induced mouse locomotor activity were both enhanced by genetic deletion of Cav-1. Interestingly, genetic deletion of Cav-1 rendered the atypical antipsychotics clozapine and olanzapine and the 5-HT 2A -selective antagonist M100907 ineffective at normalizing PCP-induced disruption of PPI. We also discovered that genetic deletion of Cav-1 attenuated 5-HT 2A -induced c-Fos and egr-1 expression in mouse frontal cortex and also reduced 5-HT 2A -mediated Ca 2 mobilization in primary cortical neuronal cultures. The behavioral effects of the 5-HT 2A agonist (2,5-dimethoxy-4-iodoamphetamine) including head twitch responses and disruption of PPI were also attenuated by genetic deletion of Cav-1, indicating that Cav-1 is required for both inverse agonist (that is, atypical antipsychotic drug) and agonist actions at 5-HT 2A receptors. This study demonstrates that disruption of the CAV1 genea rare structural variant associated with schizophreniais not only pro-psychotic but also attenuates atypical antipsychotic drug actions.

Original languageEnglish (US)
Article numbere33
JournalTranslational psychiatry
Volume1
DOIs
StatePublished - Sep 7 2011
Externally publishedYes

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Keywords

  • 5-HT2A
  • antipsychotic
  • caveolin
  • clozapine
  • schizophrenia

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Biological Psychiatry

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