Brain volumetric alterations accompanied with loss of striatal medium-sized spiny neurons and cortical parvalbumin expressing interneurons in Brd1^+/- mice.

Schizophrenia is a common and severe mental disorder arising from complex gene-environment interactions affecting brain development and functioning. While a consensus on the neuroanatomical correlates of schizophrenia is emerging, much of its fundamental pathobiology remains unknown. In this study, we explore brain morphometry in mice with genetic susceptibility and phenotypic relevance to schizophrenia (Brd1^+/- mice) using postmortem 3D MR imaging coupled with histology, immunostaining and regional mRNA marker analysis. In agreement with recent large-scale schizophrenia neuroimaging studies, Brd1^+/- mice displayed subcortical abnormalities, including volumetric reductions of amygdala and striatum. Interestingly, we demonstrate that structural alteration in striatum correlates with a general loss of striatal neurons, differentially impacting subpopulations of medium-sized spiny neurons and thus potentially striatal output. Akin to parvalbumin interneuron dysfunction in patients, a decline in parvalbumin expression was noted in the developing cortex of Brd1^+/- mice, mainly driven by neuronal loss within or near cortical layer V, which is rich in corticostriatal projection neurons. Collectively, our study highlights the translational value of the Brd1^+/- mouse as a pre-clinical tool for schizophrenia research and provides novel insight into its developmental, structural, and cellular pathology.

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