Postnatal Loss of Hap1 Reduces Hippocampal Neurogenesis and Causes Adult Depressive-Like Behavior in Mice

• Type of Material: Article
• Authors: Jianxing Xiang, Emory University; Sen Yan, Chinese Academy of Sciences; Shihua Li, Emory University; Xiao-Jiang Li, Emory University
• Language: English
• Date: 2015-04-15
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2015 Xiang et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pgen.1005175
• Title of Journal or Parent Work: PLoS Genetics
• ISSN: 1553-7390
• Volume: 11
• Issue: 4
• Start Page: e1005175
• End Page: e1005175
• Grant/Funding Information: This work was supported by grants from the National Institutes of Health (NS036232, NS041669 and AG019206).
• Research Categories: Biology, Neuroscience; Biology, Genetics; Health Sciences, Mental Health

Abstract

Depression is a serious mental disorder that affects a person’s mood, thoughts, behavior, physical health, and life in general. Despite our continuous efforts to understand the disease, the etiology of depressive behavior remains perplexing. Recently, aberrant early life or postnatal neurogenesis has been linked to adult depressive behavior; however, genetic evidence for this is still lacking. Here we genetically depleted the expression of huntingtin-associated protein 1 (Hap1) in mice at various ages or in selective brain regions. Depletion of Hap1 in the early postnatal period, but not later life, led to a depressive-like phenotype when the mice reached adulthood. Deletion of Hap1 in adult mice rendered the mice more susceptible to stress-induced depressive-like behavior. Furthermore, early Hap1 depletion impaired postnatal neurogenesis in the dentate gyrus (DG) of the hippocampus and reduced the level of c-kit, a protein expressed in neuroproliferative zones of the rodent brain and that is stabilized by Hap1. Importantly, stereotaxically injected adeno-associated virus (AAV) that directs the expression of c-kit in the hippocampus promoted postnatal hippocampal neurogenesis and ameliorated the depressive-like phenotype in conditional Hap1 KO mice, indicating a link between postnatal-born hippocampal neurons and adult depression. Our results demonstrate critical roles for Hap1 and c-kit in postnatal neurogenesis and adult depressive behavior, and also suggest that genetic variations affecting postnatal neurogenesis may lead to adult depression.