title: Dysbindin-1 mutant mice implicate reduced fast-phasic inhibition as a final common disease mechanism in schizophrenia.
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.
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104-3403, USA. gregc@mail.med.upenn.edu
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Carlson
authors.forename: Konrad
authors.initials: K
authors.lastname: Talbot
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Halene
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gandal
authors.forename: Hala A
authors.initials: HA
authors.lastname: Kazi
authors.forename: Laura
authors.initials: L
authors.lastname: Schlosser
authors.forename: Quan H
authors.initials: QH
authors.lastname: Phung
authors.forename: Raquel E
authors.initials: RE
authors.lastname: Gur
authors.forename: Steven E
authors.initials: SE
authors.lastname: Arnold
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Siegel
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D004594:Electrophysiology; D005072:Evoked Potentials, Auditory / Q000235:genetics / Q000502:physiology*; D005260:Female; D005838:Genotype; D007150:Immunohistochemistry; D008032:Limbic System / Q000378:metabolism*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D010320:Parvalbumins; D012559:Schizophrenia / Q000235:genetics*; D013569:Synapses / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; C498992:Dtnbp1 protein, mouse; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D010320:Parvalbumins