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Interplay between DISC1 and GABA Signaling Regulates Neurogenesis in Mice and Risk for Schizophrenia
Interplay between DISC1 and GABA Signaling Regulates Neurogenesis in Mice and Risk for Schizophrenia
- Source :
- Cell. 148(5):1051-1064
- Publication Year :
- 2012
- Publisher :
- Elsevier BV, 2012.
-
Abstract
- SummaryHow 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.
- Subjects :
- Sodium-Potassium-Chloride Symporters
Neurogenesis
Nerve Tissue Proteins
Hippocampal formation
General Biochemistry, Genetics and Molecular Biology
gamma-Aminobutyric acid
Article
DISC1
Mice
medicine
Animals
Solute Carrier Family 12, Member 2
PI3K/AKT/mTOR pathway
gamma-Aminobutyric Acid
biology
Biochemistry, Genetics and Molecular Biology(all)
Depolarization
Anatomy
Dendrites
Hyperpolarization (biology)
Mice, Inbred C57BL
biology.protein
Schizophrenia
Female
Disease Susceptibility
Signal transduction
Single-Cell Analysis
Neuroscience
medicine.drug
Signal Transduction
Subjects
Details
- ISSN :
- 00928674
- Volume :
- 148
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Cell
- Accession number :
- edsair.doi.dedup.....547c7b0e1ab9f65d9a15e31b11b82059
- Full Text :
- https://doi.org/10.1016/j.cell.2011.12.037