Copy number elevation of 22q11.2 genes arrests the developmental maturation of working memory capacity and adult hippocampal neurogenesis

S. Boku, T. Izumi, S. Abe, T. Takahashi, A. Nishi, H. Nomaru, Y. Naka, G. Kang, M. Nagashima, A. Hishimoto, S. Enomoto, G. Duran-Torres, K. Tanigaki, Jinghang Zhang, Qian K. Ye, S. Kato, P. T. Männistö, K. Kobayashi, Noboru Hiroi

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Working memory capacity, a critical component of executive function, expands developmentally from childhood through adulthood. Anomalies in this developmental process are seen in individuals with autism spectrum disorder (ASD), schizophrenia and intellectual disabilities (ID), implicating this atypical process in the trajectory of developmental neuropsychiatric disorders. However, the cellular and neuronal substrates underlying this process are not understood. Duplication and triplication of copy number variants of 22q11.2 are consistently and robustly associated with cognitive deficits of ASD and ID in humans, and overexpression of small 22q11.2 segments recapitulates dimensional aspects of developmental neuropsychiatric disorders in mice. We capitalized on these two lines of evidence to delve into the cellular substrates for this atypical development of working memory. Using a region- and cell-type-selective gene expression approach, we demonstrated that copy number elevations of catechol-O-methyl-transferase (COMT) or Tbx1, two genes encoded in the two small 22q11.2 segments, in adult neural stem/progenitor cells in the hippocampus prevents the developmental maturation of working memory capacity in mice. Moreover, copy number elevations of COMT or Tbx1 reduced the proliferation of adult neural stem/progenitor cells in a cell-autonomous manner in vitro and migration of their progenies in the hippocampus granular layer in vivo. Our data provide evidence for the novel hypothesis that copy number elevations of these 22q11.2 genes alter the developmental trajectory of working memory capacity via suboptimal adult neurogenesis in the hippocampus.

Original languageEnglish (US)
Pages (from-to)985-992
Number of pages8
JournalMolecular Psychiatry
Volume23
Issue number4
DOIs
StatePublished - Apr 1 2018

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Developmental Genes
Neurogenesis
Short-Term Memory
Guaiacol
Hippocampus
Adult Stem Cells
Neural Stem Cells
Transferases
Intellectual Disability
Stem Cells
Executive Function
Schizophrenia
Gene Expression
Genes
Autism Spectrum Disorder

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Copy number elevation of 22q11.2 genes arrests the developmental maturation of working memory capacity and adult hippocampal neurogenesis. / Boku, S.; Izumi, T.; Abe, S.; Takahashi, T.; Nishi, A.; Nomaru, H.; Naka, Y.; Kang, G.; Nagashima, M.; Hishimoto, A.; Enomoto, S.; Duran-Torres, G.; Tanigaki, K.; Zhang, Jinghang; Ye, Qian K.; Kato, S.; Männistö, P. T.; Kobayashi, K.; Hiroi, Noboru.

In: Molecular Psychiatry, Vol. 23, No. 4, 01.04.2018, p. 985-992.

Research output: Contribution to journalArticle

Boku, S, Izumi, T, Abe, S, Takahashi, T, Nishi, A, Nomaru, H, Naka, Y, Kang, G, Nagashima, M, Hishimoto, A, Enomoto, S, Duran-Torres, G, Tanigaki, K, Zhang, J, Ye, QK, Kato, S, Männistö, PT, Kobayashi, K & Hiroi, N 2018, 'Copy number elevation of 22q11.2 genes arrests the developmental maturation of working memory capacity and adult hippocampal neurogenesis', Molecular Psychiatry, vol. 23, no. 4, pp. 985-992. https://doi.org/10.1038/mp.2017.158
Boku, S. ; Izumi, T. ; Abe, S. ; Takahashi, T. ; Nishi, A. ; Nomaru, H. ; Naka, Y. ; Kang, G. ; Nagashima, M. ; Hishimoto, A. ; Enomoto, S. ; Duran-Torres, G. ; Tanigaki, K. ; Zhang, Jinghang ; Ye, Qian K. ; Kato, S. ; Männistö, P. T. ; Kobayashi, K. ; Hiroi, Noboru. / Copy number elevation of 22q11.2 genes arrests the developmental maturation of working memory capacity and adult hippocampal neurogenesis. In: Molecular Psychiatry. 2018 ; Vol. 23, No. 4. pp. 985-992.
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