The primary aim of this laboratory is to more fully understand the genetic, cellular and molecular mechanisms of developmental neuropsychiatric disorders.  Copy number variations (CNVs) are associated with high rates of autism spectrum disorder, intellectual disability, and schizophrenia. Because CNVs include many individual genes, it is not possible to determine whether chromosomal segments or single genes are responsible for specific dimensional aspects of developmental neuropsychiatric disorders in humans. To circumvent this obstacle, our laboratory examines the role of chromosomal segments within CNVs and individual CNV-encoded genes in behavioral and cellular phenotypes in cell and mouse models. 

1) Hiroi N., Zhu H., Lee M., Funke B., Arai M., Itokawa M., Kucherlapati R., Morrow B., Sawamura T., Agatsuma S. A 200-kb region of human chromosome 22q11.2 confers antipsychotic-responsive behavioral abnormalities in mice. Proc. Natl. Acad. Sci. USA102(52), 19132-19137, 2005.

2) Suzuki,G., Harper, K., Hiramoto, T., Lee, M., Kang, G., Kinoshita, M., Tanigaki, M., Buell, M., Geyer, M., Trimble, W., Agatsuma, S., Hiroi, N. Sept5 deficiency exerts pleiotropic influence on social and affective behaviors and cognitive functions in mice. Human Molecular Genetics, 18(9):1652-60, 2009.

3) Suzuki, G.,  Harper,K.M., Hiramoto, T.,  Funke, B., Lee, M.S., Kang, G., Buell, M., Geyer, M.A.,  Kucherlapati, R., Morrow, B., Männistö, P.T., Agatsuma, S., Hiroi, N. Over-expression of a human chromosome 22q11.2 segment including TXNRD2, COMT, and ARVCF developmentally affects incentive learning and working memory in mice. Human Molecular Genetics,18(20):3914-25, 2009.

4) Hiramoto, T., Kang, G., Suzuki, G., Satoh, Y., Kucherlapati, R., Watanabe, Y., Hiroi, N. Tbx1: identification of a 22q11.2 gene as a risk factor for autism spectrum disorder in a mouse model. Human Molecular Genetics, 20(24):4775-85 2011.

5) Harper, K.M., Hiramoto, T., Tanigaki, K., Kang, G., Suzuki, G., Trimble, W., Hiroi, N. Alterations of social interaction through genetic and environmental manipulation of the 22q11.2 gene Sept5 in the mouse brain. Human Molecular Genetics 21(15): 3489-3499, 2012. 

6) Hiroi, N., Hiramoto, T., Harper, K.M., Suzuki, G., Boku, S. Mouse Models of 22q11.2-associated Autism Spectrum Disorder. Autism  S1:001, 1-9, 2012  http://dx.doi.org/10.4172/2165-7890.S1-001

7) Hiroi, N., Takahashi, T., Hishimoto, A., Izumi, A. Boku, S., Hiramoto, T.  Copy Number Variation at 22q11.2: from rare variants to common mechanisms of developmental neuropsychiatric disorders. Molecular Psychiatry 18: 1153-1165, 2013.

8) Hiroi, N. Small Cracks in the Dam: Rare genetic variants provide opportunities to delve into mechanisms of neuropsychiatric disorders. Biological Psychiatry 76(2):91-2, 2014.

9) Boku, S., Toda, H., Nakagawa, S, Kato, A., Inoue, T., Koyama, K., Hiroi, N.,  Kusumi, I. Neonatal maternal separation alters the capacity of adult neural precursor cells to differentiate into neurons via methylation of retinoic acid receptor gene promoter. Biological Psychiatry77(4) 335-344, 2015.

10) Takahashi, T., Okabe, S., Ó Broin, P., Nishi, A., Ye, K., Beckert, M.V., Izumi, T.,  Machida, A., Kang, G., Pena, JL., Golden, A., Kikusui, K., Hiroi, N. Structure and function of neonatal social communication in a genetic mouse model of autism. Molecular Psychiatry. 21(9):1208-14, 2016.

11) Kikusui, T. and Hiroi, N.  A self-generated environmental factor as a potential contributor to atypical early social communication in autism.  Neuropsychopharmacology 42(1), 378 (2017)Online published in December 2016.

12) Esposito, G., Hiroi, N., Scattoni, M.L. Cry, baby, cry: Expression of distress as a biomarker and modulator in Autism Spectrum Disorder. International Journal of Neuropsychopharmacology (2017 in press).

13) Boku, S, Izumi, T., Abe, S., Takahashi, T., Nishi, A., Naka, Y., Nomaru, H., Kang, G., Hishimoto, A., Duran-Torres, G., Tanigaki, K., Zhang, Z., Ye, K., K., Nagashima, M, Enomoto, S., Kato, S., Ma¨nnisto, P.,  Kobayashi, K., Mannisto, P. Hiroi, N. Copy number elevation of 22q11.2 genes arrests the developmental maturation of working memory capacity and adult neurogenesis. Molecular Psychiatry (in press).