title: Schizophrenia risk gene CAV1 is both pro-psychotic and required for atypical antipsychotic drug actions in vivo.
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 gene--a rare structural variant associated with schizophrenia--is not only pro-psychotic but also attenuates atypical antipsychotic drug actions.
authors: Department of Pharmacology, University of North Carolina, Schools of Medicine and Pharmacy, Chapel Hill, NC 27599-7365, USA.
authors: J A
authors: JA
authors: Allen
authors: P N
authors: PN
authors: Yadav
authors: V
authors: V
authors: Setola
authors: M
authors: M
authors: Farrell
authors: B L
authors: BL
authors: Roth
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D051242:Caveolin 1 / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D004195:Disease Models, Animal; D051379:Mice; D018345:Mice, Knockout; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics; D012559:Schizophrenia / Q000209:etiology* / Q000235:genetics* / Q000503:physiopathology
chemical_list: D014150:Antipsychotic Agents; D051242:Caveolin 1; D044402:Receptor, Serotonin, 5-HT2A