PMID- 24747217 OWN - NLM STAT- MEDLINE DCOM- 20150109 LR - 20211021 IS - 1876-7753 (Electronic) IS - 1873-5061 (Print) IS - 1873-5061 (Linking) VI - 12 IP - 3 DP - 2014 May TI - VGF (TLQP-62)-induced neurogenesis targets early phase neural progenitor cells in the adult hippocampus and requires glutamate and BDNF signaling. PG - 762-77 LID - S1873-5061(14)00032-4 [pii] LID - 10.1016/j.scr.2014.03.005 [doi] AB - The neuropeptide VGF (non-acronymic), which has antidepressant-like effects, enhances adult hippocampal neurogenesis as well as synaptic activity and plasticity in the hippocampus, however the interaction between these processes and the mechanism underlying this regulation remain unclear. In this study, we demonstrate that VGF-derived peptide TLQP-62 specifically enhances the generation of early progenitor cells in nestin-GFP mice. Specifically, TLQP-62 significantly increases the number of Type 2a neural progenitor cells (NPCs) while reducing the number of more differentiated Type 3 cells. The effect of TLQP-62 on proliferation rather than differentiation was confirmed using NPCs in vitro; TLQP-62 but not scrambled peptide PEHN-62 increases proliferation in a cell line as well as in primary progenitors from adult hippocampus. Moreover, TLQP-62 but not scrambled peptide increases Cyclin D mRNA expression. The proliferation of NPCs induced by TLQP-62 requires synaptic activity, in particular through NMDA and metabotropic glutamate receptors. The activation of glutamate receptors by TLQP-62 activation induces phosphorylation of CaMKII through NMDA receptors and protein kinase D through metabotropic glutamate receptor 5 (mGluR5). Furthermore, pharmacological antagonists to CaMKII and PKD inhibit TLQP-62-induced proliferation of NPCs indicating that these signaling molecules downstream of glutamate receptors are essential for the actions of TLQP-62 on neurogenesis. We also show that TLQP-62 gradually activates Brain-Derived Neurotrophic Factor (BDNF)-receptor TrkB in vitro and that Trk signaling is required for TLQP-62-induced proliferation of NPCs. Understanding the precise molecular mechanism of how TLQP-62 influences neurogenesis may reveal mechanisms by which VGF-derived peptides act as antidepressant-like agents. CI - Copyright (c) 2014. Published by Elsevier B.V. FAU - Thakker-Varia, Smita AU - Thakker-Varia S AD - Department of Neuroscience and Cell Biology, Rutgers University - Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA. Electronic address: varia@rutgers.edu. FAU - Behnke, Joseph AU - Behnke J AD - Department of Neuroscience and Cell Biology, Rutgers University - Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA. Electronic address: jabehnke@eden.rutgers.edu. FAU - Doobin, David AU - Doobin D AD - Department of Neuroscience and Cell Biology, Rutgers University - Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA. Electronic address: djd2148@columbia.edu. FAU - Dalal, Vidhi AU - Dalal V AD - Department of Neuroscience and Cell Biology, Rutgers University - Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA. Electronic address: vdalal89@gmail.com. FAU - Thakkar, Keya AU - Thakkar K AD - Department of Neuroscience and Cell Biology, Rutgers University - Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA. Electronic address: kthakkar90@gmail.com. FAU - Khadim, Farah AU - Khadim F AD - Department of Neuroscience and Cell Biology, Rutgers University - Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA. Electronic address: farah.khadim@gmail.com. FAU - Wilson, Elizabeth AU - Wilson E AD - Department of Neuroscience and Cell Biology, Rutgers University - Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA. Electronic address: liz.v.wilson@gmail.com. FAU - Palmieri, Alicia AU - Palmieri A AD - Department of Neuroscience and Cell Biology, Rutgers University - Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA. Electronic address: palmieaj@rwjms.rutgers.edu. FAU - Antila, Hanna AU - Antila H AD - Neuroscience Center, University of Helsinki, P.O. Box 56, Viikinkaari 4, 00014 Helsinki, Finland. Electronic address: hanna.antila@helsinki.fi. FAU - Rantamaki, Tomi AU - Rantamaki T AD - Neuroscience Center, University of Helsinki, P.O. Box 56, Viikinkaari 4, 00014 Helsinki, Finland. Electronic address: tomi.rantamaki@helsinki.fi. FAU - Alder, Janet AU - Alder J AD - Department of Neuroscience and Cell Biology, Rutgers University - Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA. Electronic address: janet.alder@rutgers.edu. LA - eng GR - R01 MH083857/MH/NIMH NIH HHS/United States GR - R01MH083857-03/MH/NIMH NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20140326 PL - England TA - Stem Cell Res JT - Stem cell research JID - 101316957 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Neuropeptides) RN - 0 (Peptides) RN - 0 (Receptors, Glutamate) RN - 0 (TLQP62 peptide) RN - 0 (VGF peptide) RN - 3KX376GY7L (Glutamic Acid) RN - EC 2.7.10.1 (Receptor, trkA) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/*metabolism MH - Cell Proliferation MH - Glutamic Acid/*metabolism MH - Hippocampus/cytology/*metabolism MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Neural Stem Cells/cytology/*metabolism MH - *Neurogenesis MH - Neuropeptides/*metabolism MH - Peptides/*metabolism MH - Phosphorylation MH - Receptor, trkA/metabolism MH - Receptors, Glutamate/metabolism MH - *Signal Transduction PMC - PMC4991619 MID - NIHMS809465 COIS- Declaration of interest The authors report no conflicts of interest. This study was supported by the New Jersey Commission on Brain Injury Research (08-3205 BIR-E-1) and an Alpha Omega Alpha Carolyn L. Kuckein Student Research Fellowship. EDAT- 2014/04/22 06:00 MHDA- 2015/01/13 06:00 PMCR- 2016/08/19 CRDT- 2014/04/22 06:00 PHST- 2013/09/30 00:00 [received] PHST- 2014/02/24 00:00 [revised] PHST- 2014/03/18 00:00 [accepted] PHST- 2014/04/22 06:00 [entrez] PHST- 2014/04/22 06:00 [pubmed] PHST- 2015/01/13 06:00 [medline] PHST- 2016/08/19 00:00 [pmc-release] AID - S1873-5061(14)00032-4 [pii] AID - 10.1016/j.scr.2014.03.005 [doi] PST - ppublish SO - Stem Cell Res. 2014 May;12(3):762-77. doi: 10.1016/j.scr.2014.03.005. Epub 2014 Mar 26.