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Interplay between DISC1 and GABA signaling regulates neurogenesis in mice and risk for schizophrenia |
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| Authors: | Kim Ju Young Liu Cindy Y Zhang Fengyu Duan Xin Wen Zhexing Song Juan Feighery Emer Lu Bai Rujescu Dan St Clair David Christian Kimberly Callicott Joseph H Weinberger Daniel R Song Hongjun Ming Guo-li |
| Institution: | 1 Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA 2 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA 3 The Solomon Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA 4 Gene, Cognition and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA 5 Department of Psychiatry, Ludwig-Maximilians-University, Nußbaumstrasse 7, 80336, München, Germany 6 University of Aberdeen Royal Cornhill Hospital, Aberdeen AB25 2ZD, UK 7 Lieber Institute for Brain Development, Baltimore, MD 21205, USA |
| 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. |
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