title: Structural and functional neuroimaging phenotypes in dysbindin mutant mice.
abstract: Schizophrenia is a highly heritable psychiatric disorder that is associated with a number of structural and functional neurophenotypes. DTNBP1, the gene encoding dysbindin-1, is a promising candidate gene for schizophrenia. Use of a mouse model carrying a large genomic deletion exclusively within the dysbindin gene permits a direct investigation of the gene in isolation. Here, we use manganese-enhanced magnetic resonance imaging (MEMRI) to explore the regional alterations in brain structure and function caused by loss of the gene encoding dysbindin-1. We report novel findings that uniquely inform our understanding of the relationship of dysbindin-1 to known schizophrenia phenotypes. First, in mutant mice, analysis of the rate of manganese uptake into the brain over a 24-hour period, putatively indexing basal cellular activity, revealed differences in dopamine rich brain regions, as well as in CA1 and dentate subregions of the hippocampus formation. Finally, novel tensor-based morphometry techniques were applied to the mouse MRI data, providing evidence for structural volume deficits in cortical regions, subiculum and dentate gyrus, and the striatum of dysbindin mutant mice. The affected cortical regions were primarily localized to the sensory cortices in particular the auditory cortex. This work represents the first application of manganese-enhanced small animal imaging to a mouse model of schizophrenia endophenotypes, and a novel combination of functional and structural measures. It revealed both hypothesized and novel structural and functional neural alterations related to dysbindin-1.
authors.affiliation: Interdisciplinary Neuroscience Program, University of California, Los Angeles, CA 90095, USA.
authors.forename: Evan
authors.initials: E
authors.lastname: Lutkenhoff
authors.forename: Katherine H
authors.initials: KH
authors.lastname: Karlsgodt
authors.forename: Boris
authors.initials: B
authors.lastname: Gutman
authors.forename: Jason L
authors.initials: JL
authors.lastname: Stein
authors.forename: Paul M
authors.initials: PM
authors.lastname: Thompson
authors.forename: Tyrone D
authors.initials: TD
authors.lastname: Cannon
authors.forename: J David
authors.initials: JD
authors.lastname: Jentsch
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology* / Q000503:physiopathology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D012559:Schizophrenia / Q000473:pathology* / Q000503:physiopathology*
chemical_list: D002352:Carrier Proteins; C498992:Dtnbp1 protein, mouse; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins