ABSTRACT
Disrupted-in-schizophrenia 1 (DISC1), a susceptibility gene for major mental illnesses, regulates multiple aspects of embryonic and adult neurogenesis. Here, we show that DISC1 suppression in newborn neurons of the adult hippocampus leads to overactivated signaling of AKT, another schizophrenia susceptibility gene. Mechanistically, DISC1 directly interacts with KIAA1212, an AKT binding partner that enhances AKT signaling in the absence of DISC1, and DISC1 binding to KIAA1212 prevents AKT activation in vitro. Functionally, multiple genetic manipulations to enhance AKT signaling in adult-born neurons in vivo exhibit similar defects as DISC1 suppression in neuronal development that can be rescued by pharmacological inhibition of mammalian target of rapamycin (mTOR), an AKT downstream effector. Our study identifies the AKT-mTOR signaling pathway as a critical DISC1 target in regulating neuronal development and provides a framework for understanding how multiple susceptibility genes may functionally converge onto a common pathway in contributing to the etiology of certain psychiatric disorders.
Subject(s)
Hippocampus/growth & development , Nerve Tissue Proteins/physiology , Neurogenesis/physiology , Neurons/physiology , Oncogene Protein v-akt/metabolism , Signal Transduction/physiology , Adult Stem Cells/drug effects , Adult Stem Cells/metabolism , Analysis of Variance , Animals , Animals, Newborn , Cell Movement/drug effects , Cell Movement/physiology , Cells, Cultured , Female , Gene Expression Regulation, Developmental/drug effects , Gene Expression Regulation, Developmental/genetics , Gene Knockdown Techniques , Green Fluorescent Proteins/genetics , Hippocampus/cytology , Humans , Immunoprecipitation/methods , Immunosuppressive Agents/pharmacology , Mice , Mice, Inbred C57BL , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neurogenesis/drug effects , Pregnancy , Protein Binding/genetics , RNA Interference , Signal Transduction/drug effects , Sirolimus/pharmacology , Transfection/methodsABSTRACT
The mammalian brain exhibits diverse types of neural plasticity, including activity-dependent neurogenesis in the adult hippocampus. How transient activation of mature neurons leads to long-lasting modulation of adult neurogenesis is unknown. Here we identify Gadd45b as a neural activity-induced immediate early gene in mature hippocampal neurons. Mice with Gadd45b deletion exhibit specific deficits in neural activity-induced proliferation of neural progenitors and dendritic growth of newborn neurons in the adult hippocampus. Mechanistically, Gadd45b is required for activity-induced DNA demethylation of specific promoters and expression of corresponding genes critical for adult neurogenesis, including brain-derived neurotrophic factor and fibroblast growth factor. Thus, Gadd45b links neuronal circuit activity to epigenetic DNA modification and expression of secreted factors in mature neurons for extrinsic modulation of neurogenesis in the adult brain.
