Schizophrenia risk gene CAV1 is both pro-psychotic and required for atypical antipsychotic drug actions in vivo
Open accessAbstract
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.
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Current models of schizophrenia suggest that the disorder is due to both common and rare gene mutations, copy-number variations, and possibly epigenetic factors, all of which can affect multiple brain neurotransmitter systems and multiple risk genes.
“Current models of schizophrenia suggest that the disorder is due to both common and rare gene mutations, copy-number variations, and possibly epigenetic factors [361], all of which can affect multiple brain neurotransmitter systems and multiple risk genes [362-364].”
From Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings (2012) · cites this paper as [362]
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- Authors
- Allen, J. A., Yadav, P. N., Setola, V, Farrell, M., & Roth, B. L.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Roth, B L
- Venue
- Translational Psychiatry
- Published
- 2011-08-16
- Volume
- 1
- Issue
- 8
- Pages
- e33-e33
- ISSN
- 2158-3188 (ISSN-L)
- PMC
- PMC3309505
- OpenAlex
- W2094447888
- Cited by
- 37
- References
- 38
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 6 · 2021: 3 · 2020: 5 · 2019: 1 · 2018: 1 · 2017: 4 · 2016: 3 · 2015: 3 · 2014: 2 · 2012: 1
- FWCI
- 0.86
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (unspecified)
- Locations
- Translational Psychiatry (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion, cc-by-nc-nd)
- UNC Libraries
- Funders
- National Institutes of Health (HHSN-271-2008-00025-C)
- U.S. Public Health Service (HHSN-271-2008-00025-C)
- National Institute of Mental Health (U19MH082441, R01MH061887, F31MH091921)
- National Institute on Drug Abuse (R01DA017204)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD040127)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Caveolin-1 and cellular processes
- Keywords
- caveolin-1, schizophrenia, schizophrenia risk genes, phencyclidine, prepulse inhibition, atypical antipsychotics, clozapine, olanzapine, M100907, 5-HT2A receptor, inverse agonism, c-fos, EGR1, calcium mobilization, frontal cortex, knockout mice
- MeSH terms
- Animals, Behavior, Animal, Disease Models, Animal, Schizophrenia, Antipsychotic Agents, Mice, Knockout, Receptor, Serotonin, 5-HT2A, Caveolin 1, Mice
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