Structural and functional neuroimaging phenotypes in dysbindin mutant mice

• Published in: NeuroImage (Orlando, Fla.) Fla.), 2012-08, Vol.62 (1), p.120-129
• Main Authors: Lutkenhoff, Evan, Karlsgodt, Katherine H., Gutman, Boris, Stein, Jason L., Thompson, Paul M., Cannon, Tyrone D., Jentsch, J. David
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Brain; Brain - pathology; Brain - physiopathology; Carrier Proteins - genetics; Carrier Proteins - metabolism; Disease Models, Animal; Dopamine; DTNBP1; Dysbindin; Dystrophin-Associated Proteins; Genetic models; Haplotypes; Humans; Manganese; Medical imaging; Mice; Mice, Transgenic; Mutation - genetics; Neuroimaging; Proteins; Rodents; Schizophrenia; Schizophrenia - pathology; Schizophrenia - physiopathology; Studies
• ISSN: 1053-8119; 1095-9572
• DOI: 10.1016/j.neuroimage.2012.05.008

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. ►Dysbindin (DTNBP1) is a promising candidate gene for schizophrenia. ►DNTBP1 has been associated with neural and cognitive changes in humans and mice. ►This is the first application of neuroimaging to a dysbindin mouse model. ►We observed functional changes in the hippocampus and dopaminergic circuitry. ►We also observed structural changes in cortical and subcortical volumes.