Interplay between DISC1 and GABA signaling regulates neurogenesis in mice and risk for schizophrenia

Ju Young Kim, Cindy Y Liu, Fengyu Zhang, Xin Duan, Zhexing Wen, Juan Song, Emer Feighery, Bai Lu, Dan Rujescu, David St Clair, Kimberly Christian, Joseph H Callicott, Daniel R Weinberger, Hongjun Song, Guo-li Ming

Research output: Contribution to journalArticle

140 Citations (Scopus)

Abstract

How extrinsic stimuli and intrinsic factors interact to regulate continuous neurogenesis in the postnatal mammalian brain is unknown. Here we show that regulation of dendritic development of newborn neurons by Disrupted-in-Schizophrenia 1 (DISC1) during adult hippocampal neurogenesis requires neurotransmitter GABA-induced, NKCC1-dependent depolarization through a convergence onto the AKT-mTOR pathway. In contrast, DISC1 fails to modulate early-postnatal hippocampal neurogenesis when conversion of GABA-induced depolarization to hyperpolarization is accelerated. Extending the period of GABA-induced depolarization or maternal deprivation stress restores DISC1-dependent dendritic regulation through mTOR pathway during early-postnatal hippocampal neurogenesis. Furthermore, DISC1 and NKCC1 interact epistatically to affect risk for schizophrenia in two independent case control studies. Our study uncovers an interplay between intrinsic DISC1 and extrinsic GABA signaling, two schizophrenia susceptibility pathways, in controlling neurogenesis and suggests critical roles of developmental tempo and experience in manifesting the impact of susceptibility genes on neuronal development and risk for mental disorders.
Original languageEnglish
Pages (from-to)1051-1064
Number of pages14
JournalCell
Volume148
Issue number5
DOIs
Publication statusPublished - Mar 2012

Keywords

  • Animals
  • Dendrites
  • Disease Susceptibility
  • Female
  • Mice
  • Mice, Inbred C57BL
  • Nerve Tissue Proteins
  • Neurogenesis
  • Schizophrenia
  • Signal Transduction
  • Single-Cell Analysis
  • Sodium-Potassium-Chloride Symporters
  • gamma-Aminobutyric Acid

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    Kim, J. Y., Liu, C. Y., Zhang, F., Duan, X., Wen, Z., Song, J., Feighery, E., Lu, B., Rujescu, D., St Clair, D., Christian, K., Callicott, J. H., Weinberger, D. R., Song, H., & Ming, G. (2012). Interplay between DISC1 and GABA signaling regulates neurogenesis in mice and risk for schizophrenia. Cell, 148(5), 1051-1064. https://doi.org/10.1016/j.cell.2011.12.037