title: VGF (TLQP-62)-induced neurogenesis targets early phase neural progenitor cells in the adult hippocampus and requires glutamate and BDNF signaling.
abstract: 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.
authors.affiliation: Department of Neuroscience and Cell Biology, Rutgers University - Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA. Electronic address: varia@rutgers.edu.
authors.forename: Smita
authors.initials: S
authors.lastname: Thakker-Varia
authors.affiliation: Department of Neuroscience and Cell Biology, Rutgers University - Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA. Electronic address: jabehnke@eden.rutgers.edu.
authors.forename: Joseph
authors.initials: J
authors.lastname: Behnke
authors.affiliation: Department of Neuroscience and Cell Biology, Rutgers University - Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA. Electronic address: djd2148@columbia.edu.
authors.forename: David
authors.initials: D
authors.lastname: Doobin
authors.affiliation: Department of Neuroscience and Cell Biology, Rutgers University - Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA. Electronic address: vdalal89@gmail.com.
authors.forename: Vidhi
authors.initials: V
authors.lastname: Dalal
authors.affiliation: Department of Neuroscience and Cell Biology, Rutgers University - Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA. Electronic address: kthakkar90@gmail.com.
authors.forename: Keya
authors.initials: K
authors.lastname: Thakkar
authors.affiliation: Department of Neuroscience and Cell Biology, Rutgers University - Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA. Electronic address: farah.khadim@gmail.com.
authors.forename: Farah
authors.initials: F
authors.lastname: Khadim
authors.affiliation: Department of Neuroscience and Cell Biology, Rutgers University - Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA. Electronic address: liz.v.wilson@gmail.com.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Wilson
authors.affiliation: Department of Neuroscience and Cell Biology, Rutgers University - Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA. Electronic address: palmieaj@rwjms.rutgers.edu.
authors.forename: Alicia
authors.initials: A
authors.lastname: Palmieri
authors.affiliation: Neuroscience Center, University of Helsinki, P.O. Box 56, Viikinkaari 4, 00014 Helsinki, Finland. Electronic address: hanna.antila@helsinki.fi.
authors.forename: Hanna
authors.initials: H
authors.lastname: Antila
authors.affiliation: Neuroscience Center, University of Helsinki, P.O. Box 56, Viikinkaari 4, 00014 Helsinki, Finland. Electronic address: tomi.rantamaki@helsinki.fi.
authors.forename: Tomi
authors.initials: T
authors.lastname: Rantamaki
authors.affiliation: Department of Neuroscience and Cell Biology, Rutgers University - Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA. Electronic address: janet.alder@rutgers.edu.
authors.forename: Janet
authors.initials: J
authors.lastname: Alder
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D049109:Cell Proliferation; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D055495:Neurogenesis; D009479:Neuropeptides / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D010766:Phosphorylation; D020917:Receptor, trkA / Q000378:metabolism; D017470:Receptors, Glutamate / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D009479:Neuropeptides; D010455:Peptides; D017470:Receptors, Glutamate; C000593377:TLQP62 peptide; C522413:VGF peptide; D018698:Glutamic Acid; D020917:Receptor, trkA
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