Cited by 103Schizophrenia research and treatmentNeuroscience and Neuropharmacology ResearchNeurotransmitter Receptor Influence on Behavior

Dysbindin-1 mutant mice implicate reduced fast-phasic inhibition as a final common disease mechanism in schizophrenia

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Carlson, Gregory C., Talbot, Konrad, Halene, Tobias B., Gandal, Michael J., Kazi, Hala A., Schlosser, Laura, Phung, Quan H., Gur, Raquel E. +2 more·2011·Proceedings of the National Academy of Sciences

Abstract

DTNBP1 (dystrobrevin binding protein 1) is a leading candidate susceptibility gene in schizophrenia and is associated with working memory capacity in normal subjects. In schizophrenia, the encoded protein dystrobrevin-binding protein 1 (dysbindin-1) is often reduced in excitatory cortical limbic synapses. We found that reduced dysbindin-1 in mice yielded deficits in auditory-evoked response adaptation, prepulse inhibition of startle, and evoked γ-activity, similar to patterns in schizophrenia. In contrast to the role of dysbindin-1 in glutamatergic transmission, γ-band abnormalities in schizophrenia are most often attributed to disrupted inhibition and reductions in parvalbumin-positive interneuron (PV cell) activity. To determine the mechanism underlying electrophysiological deficits related to reduced dysbindin-1 and the potential role of PV cells, we examined PV cell immunoreactivity and measured changes in net circuit activity using voltage-sensitive dye imaging. The dominant circuit impact of reduced dysbindin-1 was impaired inhibition, and PV cell immunoreactivity was reduced. Thus, this model provides a link between a validated candidate gene and an auditory endophenotypes. Furthermore, these data implicate reduced fast-phasic inhibition as a common underlying mechanism of schizophrenia-associated intermediate phenotypes.

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  • Preclinical animal models reproducing genetic vulnerabilities or environmental risk factors show anomalies in hippocampal and/or prefrontal parvalbumin interneurons.

    “Recent studies have revealed anomalies in hippocampal and/or prefrontal PVI in many preclinical animal models aiming to reproduce genetic vulnerabilities (Carlson et al., 2011; Fazzari et al., 2010; Hikida et al., 2007; Wen et al., 2010) or environmental risk factors (Brown, 2011) such as prenatal maternal stress (Stevens et al., 2013), maternal and perinatal immune challenge (Jenkins et al., 2009”

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Authors
Carlson, G. C., Talbot, K., Halene, T. B., Gandal, M. J., Kazi, H. A., Schlosser, L., Phung, Q. H., Gur, R. E., Arnold, S. E., & Siegel, S. J.
Affiliations
University of Pennsylvania (US)
Venue
Proceedings of the National Academy of Sciences
Published
2011-10-03
Volume
108
Issue
43
Pages
E962-70
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W2117959142
Cited by
103
References
86
Citations by year
2025: 2 · 2024: 3 · 2023: 4 · 2022: 5 · 2021: 2 · 2020: 6 · 2019: 4 · 2018: 5 · 2017: 5 · 2016: 13 · 2015: 13 · 2014: 14 · 2013: 12 · 2012: 15
FWCI
8.97
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Deutsche Forschungsgemeinschaft (IRTG1328)
  • National Institutes of Health (5r01da023210-05, 5p50mh064045-10, MH64045)
  • National Institute of Mental Health (P50 MH-064045, MH072880, R01MH072880, P50 MH 64045)
  • National Institute on Drug Abuse (R01-DA023210, 5R01-DA02321002)
  • National Cancer Institute (P50CA084718)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
dysbindin-1, DTNBP1, schizophrenia, parvalbumin interneurons, prepulse inhibition, gamma oscillations, glutamatergic neurotransmission, candidate susceptibility genes, endophenotypes, voltage-sensitive dye imaging
MeSH terms
Dysbindin, Animals, Carrier Proteins, Electrophysiology, Evoked Potentials, Auditory, Female, Genotype, Immunohistochemistry, Limbic System, Male, Mice, Mutant Strains, Parvalbumins, Schizophrenia, Synapses, Dystrophin-Associated Proteins, Mice

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