PMID- 29507199 OWN - NLM STAT- MEDLINE DCOM- 20180824 LR - 20240328 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 115 IP - 15 DP - 2018 Apr 10 TI - Antidepression action of BDNF requires and is mimicked by Galphai1/3 expression in the hippocampus. PG - E3549-E3558 LID - 10.1073/pnas.1722493115 [doi] AB - Stress-related alterations in brain-derived neurotrophic factor (BDNF) expression, a neurotrophin that plays a key role in synaptic plasticity, are believed to contribute to the pathophysiology of depression. Here, we show that in a chronic mild stress (CMS) model of depression the Galphai1 and Galphai3 subunits of heterotrimeric G proteins are down-regulated in the hippocampus, a key limbic structure associated with major depressive disorder. We provide evidence that Galphai1 and Galphai3 (Galphai1/3) are required for the activation of TrkB downstream signaling pathways. In mouse embryonic fibroblasts (MEFs) and CNS neurons, Galphai1/3 knockdown inhibited BDNF-induced tropomyosin-related kinase B (TrkB) endocytosis, adaptor protein activation, and Akt-mTORC1 and Erk-MAPK signaling. Functional studies show that Galphai1 and Galphai3 knockdown decreases the number of dendrites and dendritic spines in hippocampal neurons. In vivo, hippocampal Galphai1/3 knockdown after bilateral microinjection of lentiviral constructs containing Galphai1 and Galphai3 shRNA elicited depressive behaviors. Critically, exogenous expression of Galphai3 in the hippocampus reversed depressive behaviors in CMS mice. Similar results were observed in Galphai1/Galphai3 double-knockout mice, which exhibited severe depressive behaviors. These results demonstrate that heterotrimeric Galphai1 and Galphai3 proteins are essential for TrkB signaling and that disruption of Galphai1 or Galphai3 function could contribute to depressive behaviors. FAU - Marshall, John AU - Marshall J AD - Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI 02912; John_Marshall@Brown.edu birnbau1@gmail.com caocong@suda.edu.cn. FAU - Zhou, Xiao-Zhong AU - Zhou XZ AD - Jiangsu Key Laboratory of Neuropsychiatric Diseases Research, Soochow University, Suzhou 215000, China. AD - Institute of Neuroscience, Soochow University, Suzhou 215000, China. AD - Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, 215004 Jiangsu, China. FAU - Chen, Gang AU - Chen G AD - Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, 215006 Jiangsu, China. FAU - Yang, Su-Qing AU - Yang SQ AD - Jiangsu Key Laboratory of Neuropsychiatric Diseases Research, Soochow University, Suzhou 215000, China. AD - Institute of Neuroscience, Soochow University, Suzhou 215000, China. FAU - Li, Ya AU - Li Y AD - Jiangsu Key Laboratory of Neuropsychiatric Diseases Research, Soochow University, Suzhou 215000, China. AD - Institute of Neuroscience, Soochow University, Suzhou 215000, China. FAU - Wang, Yin AU - Wang Y AD - Jiangsu Key Laboratory of Neuropsychiatric Diseases Research, Soochow University, Suzhou 215000, China. AD - Institute of Neuroscience, Soochow University, Suzhou 215000, China. FAU - Zhang, Zhi-Qing AU - Zhang ZQ AD - Jiangsu Key Laboratory of Neuropsychiatric Diseases Research, Soochow University, Suzhou 215000, China. AD - Institute of Neuroscience, Soochow University, Suzhou 215000, China. FAU - Jiang, Qin AU - Jiang Q AD - The Fourth School of Clinical Medicine, The Affiliated Eye Hospital, Nanjing Medical University, 210029 Nanjing, China. FAU - Birnbaumer, Lutz AU - Birnbaumer L AD - Neurobiology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709; John_Marshall@Brown.edu birnbau1@gmail.com caocong@suda.edu.cn. AD - School of Medical Sciences, Institute of Biomedical Research, Catholic University of Argentina, C1107AAZ Buenos Aires, Argentina. FAU - Cao, Cong AU - Cao C AUID- ORCID: 0000-0003-0824-3472 AD - Jiangsu Key Laboratory of Neuropsychiatric Diseases Research, Soochow University, Suzhou 215000, China; John_Marshall@Brown.edu birnbau1@gmail.com caocong@suda.edu.cn. AD - Institute of Neuroscience, Soochow University, Suzhou 215000, China. AD - The Fourth School of Clinical Medicine, The Affiliated Eye Hospital, Nanjing Medical University, 210029 Nanjing, China. AD - North District, The Municipal Hospital of Suzhou, Suzhou 215001, China. LA - eng GR - R01 NS094440/NS/NINDS NIH HHS/United States GR - R21 MH104252/MH/NIMH NIH HHS/United States GR - Z01 ES101643/ImNIH/Intramural NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, N.I.H., Intramural PT - Research Support, Non-U.S. Gov't DEP - 20180305 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Brain-Derived Neurotrophic Factor) RN - EC 3.6.5.1 (GTP-Binding Protein alpha Subunit, Gi2) RN - EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gi-Go) SB - IM CIN - Proc Natl Acad Sci U S A. 2018 Apr 10;115(15):3742-3744. PMID: 29592951 MH - Animals MH - Brain-Derived Neurotrophic Factor/*metabolism MH - Dendrites/metabolism/pathology MH - Dendritic Spines/metabolism/pathology MH - Depression/*metabolism/pathology MH - Depressive Disorder, Major/metabolism/pathology MH - Down-Regulation MH - Female MH - GTP-Binding Protein alpha Subunit, Gi2/*biosynthesis/genetics/metabolism MH - GTP-Binding Protein alpha Subunits, Gi-Go/*biosynthesis/genetics/metabolism MH - Hippocampus/*metabolism MH - Mice MH - Mice, Knockout MH - Neurons/metabolism/pathology MH - Signal Transduction/drug effects MH - Stress, Physiological/physiology PMC - PMC5899481 OTO - NOTNLM OT - BDNF OT - Galphai1 OT - Galphai3 OT - depression OT - hippocampus COIS- The authors declare no conflict of interest. EDAT- 2018/03/07 06:00 MHDA- 2018/08/25 06:00 PMCR- 2018/10/10 CRDT- 2018/03/07 06:00 PHST- 2018/03/07 06:00 [pubmed] PHST- 2018/08/25 06:00 [medline] PHST- 2018/03/07 06:00 [entrez] PHST- 2018/10/10 00:00 [pmc-release] AID - 1722493115 [pii] AID - 201722493 [pii] AID - 10.1073/pnas.1722493115 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2018 Apr 10;115(15):E3549-E3558. doi: 10.1073/pnas.1722493115. Epub 2018 Mar 5.