title: Interplay between DISC1 and GABA signaling regulates neurogenesis in mice and risk for schizophrenia.
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.
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Ju Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Cindy Y
authors.initials: CY
authors.lastname: Liu
authors.forename: Fengyu
authors.initials: F
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Duan
authors.forename: Zhexing
authors.initials: Z
authors.lastname: Wen
authors.forename: Juan
authors.initials: J
authors.lastname: Song
authors.forename: Emer
authors.initials: E
authors.lastname: Feighery
authors.forename: Bai
authors.initials: B
authors.lastname: Lu
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
authors.forename: David
authors.initials: D
authors.lastname: St Clair
authors.forename: Kimberly
authors.initials: K
authors.lastname: Christian
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Callicott
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
authors.forename: Hongjun
authors.initials: H
authors.lastname: Song
authors.forename: Guo-li
authors.initials: GL
authors.lastname: Ming
mesh_terms: D000818:Animals; D003712:Dendrites / Q000378:metabolism; D004198:Disease Susceptibility; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D055495:Neurogenesis; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D059010:Single-Cell Analysis; D028021:Sodium-Potassium-Chloride Symporters / Q000235:genetics / Q000378:metabolism; D064506:Solute Carrier Family 12, Member 2; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: C412476:DISC1 protein, human; C498794:Disc1 protein, mouse; D009419:Nerve Tissue Proteins; C578877:SLC12A2 protein, human; C578878:Slc12a2 protein, mouse; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; D005680:gamma-Aminobutyric Acid