PMID- 29158577 OWN - NLM STAT- MEDLINE DCOM- 20190617 LR - 20211204 IS - 1476-5578 (Electronic) IS - 1359-4184 (Print) IS - 1359-4184 (Linking) VI - 23 IP - 7 DP - 2018 Jul TI - VGF function in depression and antidepressant efficacy. PG - 1632-1642 LID - 10.1038/mp.2017.233 [doi] AB - Brain-derived neurotrophic factor (BDNF) is a critical effector of depression-like behaviors and antidepressant responses. Here, we show that VGF (non-acronymic), which is robustly regulated by BDNF/TrkB signaling, is downregulated in hippocampus (male/female) and upregulated in nucleus accumbens (NAc) (male) in depressed human subjects and in mice subjected to chronic social defeat stress (CSDS). Adeno-associated virus (AAV)-Cre-mediated Vgf ablation in floxed VGF mice, in dorsal hippocampus (dHc) or NAc, led to pro-depressant or antidepressant behaviors, respectively, while dHc- or NAc-AAV-VGF overexpression induced opposite outcomes. Mice with reduced VGF levels in the germ line (Vgf+/-) or in dHc (AAV-Cre-injected floxed mice) showed increased susceptibility to CSDS and impaired responses to ketamine treatment in the forced swim test. Floxed mice with conditional pan-neuronal (Synapsin-Cre) but not those with forebrain (alphaCaMKII-Cre) Vgf ablation displayed increased susceptibility to subthreshold social defeat stress, suggesting that neuronal VGF, expressed in part in inhibitory interneurons, regulates depression-like behavior. Acute antibody-mediated sequestration of VGF-derived C-terminal peptides AQEE-30 and TLQP-62 in dHc induced pro-depressant effects. Conversely, dHc TLQP-62 infusion had rapid antidepressant efficacy, which was reduced in BDNF floxed mice injected in dHc with AAV-Cre, and in NBQX- and rapamycin-pretreated wild-type mice, these compounds blocking alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and mammalian target of rapamycin (mTOR) signaling, respectively. VGF is therefore a critical modulator of depression-like behaviors in dHc and NAc. In hippocampus, the antidepressant response to ketamine is associated with rapid VGF translation, is impaired by reduced VGF expression, and as previously reported, requires coincident, rapid BDNF translation and release. FAU - Jiang, C AU - Jiang C AD - Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. AD - Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Lin, W-J AU - Lin WJ AD - Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Sadahiro, M AU - Sadahiro M AD - Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. AD - Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Labonte, B AU - Labonte B AD - Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Menard, C AU - Menard C AD - Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Pfau, M L AU - Pfau ML AD - Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. AD - Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Tamminga, C A AU - Tamminga CA AD - Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA. FAU - Turecki, G AU - Turecki G AD - Department of Psychiatry, McGill University, Montreal, QC, Canada. FAU - Nestler, E J AU - Nestler EJ AD - Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. AD - Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Russo, S J AU - Russo SJ AD - Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. AD - Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Salton, S R AU - Salton SR AD - Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. stephen.salton@mssm.edu. AD - Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. stephen.salton@mssm.edu. AD - Department of Geriatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA. stephen.salton@mssm.edu. LA - eng GR - R21 MH083496/MH/NIMH NIH HHS/United States GR - R01 MH086499/MH/NIMH NIH HHS/United States GR - T32 MH087004/MH/NIMH NIH HHS/United States GR - P50 MH096890/MH/NIMH NIH HHS/United States GR - R01 MH051399/MH/NIMH NIH HHS/United States GR - R01 MH090264/MH/NIMH NIH HHS/United States GR - R33 MH083496/MH/NIMH NIH HHS/United States GR - P50 AT008661/AT/NCCIH NIH HHS/United States GR - T32 MH096678/MH/NIMH NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20171121 PL - England TA - Mol Psychiatry JT - Molecular psychiatry JID - 9607835 RN - 0 (Antidepressive Agents) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Nerve Growth Factors) RN - 0 (Neuropeptides) RN - 0 (Receptors, AMPA) RN - 0 (VGF peptide) RN - 0 (VGF protein, human) RN - 690G0D6V8H (Ketamine) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Adult MH - Animals MH - Antidepressive Agents/pharmacology MH - Brain-Derived Neurotrophic Factor/metabolism/physiology MH - Depression/*metabolism/physiopathology MH - Depressive Disorder/drug therapy MH - Down-Regulation MH - Female MH - Hippocampus/metabolism MH - Humans MH - Ketamine/pharmacology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Middle Aged MH - Nerve Growth Factors/metabolism/*physiology MH - Neurons/metabolism MH - Neuropeptides/metabolism/*physiology MH - Nucleus Accumbens/metabolism MH - Receptors, AMPA/metabolism MH - Sex Factors MH - Signal Transduction/drug effects MH - Stress, Psychological/physiopathology MH - TOR Serine-Threonine Kinases/metabolism MH - Up-Regulation PMC - PMC5962361 MID - NIHMS911893 COIS- Conflict of Interest: The authors declare no competing financial interests. EDAT- 2017/11/22 06:00 MHDA- 2019/06/18 06:00 PMCR- 2018/09/21 CRDT- 2017/11/22 06:00 PHST- 2017/02/04 00:00 [received] PHST- 2017/10/09 00:00 [accepted] PHST- 2017/09/18 00:00 [revised] PHST- 2017/11/22 06:00 [pubmed] PHST- 2019/06/18 06:00 [medline] PHST- 2017/11/22 06:00 [entrez] PHST- 2018/09/21 00:00 [pmc-release] AID - 10.1038/mp.2017.233 [pii] AID - 10.1038/mp.2017.233 [doi] PST - ppublish SO - Mol Psychiatry. 2018 Jul;23(7):1632-1642. doi: 10.1038/mp.2017.233. Epub 2017 Nov 21.