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NEUROSCIENCE
A mutation in mouse Disc1 that models a schizophrenia risk allele leads to specific alterations in neuronal architecture and cognition

Mirna Kvajo^*,, Heather McKellar, P. Alexander Arguello, Liam J. Drew, Holly Moore^*, Amy B. MacDermott^,, Maria Karayiorgou^*,¶, and Joseph A. Gogos^,,¶

Departments of *Psychiatry and Neuroscience, Columbia University Medical Center, 1051 Riverside Drive, New York, NY 10032; Department of Physiology and Cellular Biophysics, Columbia University Medical Center, 630 West 168th Street, New York, NY 10032; and Integrated Program in Cellular, Molecular, and Biophysical Studies, Columbia University, New York, NY 10032

Communicated by Gerald D. Fischbach, Columbia University College of Physicians and Surgeons, New York, NY, March 18, 2008 (received for review November 8, 2007)

Abstract

DISC1 is a strong candidate susceptibility gene for schizophrenia, bipolar disorder, and depression. Using a mouse strain carrying an endogenous Disc1 orthologue engineered to model the putative effects of the disease-associated chromosomal translocation we demonstrate that impaired Disc1 function results in region-specific morphological alterations, including alterations in the organization of newly born and mature neurons of the dentate gyrus. Field recordings at CA3/CA1 synapses revealed a deficit in short-term plasticity. Using a battery of cognitive tests we found a selective impairment in working memory (WM), which may relate to deficits in WM and executive function observed in individuals with schizophrenia. Our results implicate malfunction of neural circuits within the hippocampus and medial prefrontal cortex and selective deficits in WM as contributing to the genetic risk conferred by this gene.

bipolar disorder | gene | mouse model | working memory | adult neurogenesis

Author contributions: M. Kvajo, H. McKellar, and P.A.A. contributed equally to this work; M. Kvajo, H. McKellar, P.A.A., M. Karayiorgou, and J.A.G. designed research; M. Kvajo, H. McKellar, P.A.A., and L.J.D. performed research; H. Moore and A.B.M contributed new reagents/analytic tools; M. Kvajo, H. McKellar, P.A.A., L.J.D., H. Moore, and A.B.M. analyzed data; and M. Kvajo, H. McKellar, P.A.A., M. Karayiorgou, and J.A.G. wrote the paper.

The authors declare no conflict of interest.

^¶To whom correspondence may be addressed. E-mail: mk2758{at}columbia.edu or jag90{at}columbia.edu

© 2008 by The National Academy of Sciences of the USA

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