title: VGF and Its C-Terminal Peptide TLQP-62 Regulate Memory Formation in Hippocampus via a BDNF-TrkB-Dependent Mechanism.
abstract: Regulated expression and secretion of BDNF, which activates TrkB receptor signaling, is known to play a critical role in cognition. Identification of additional modulators of cognitive behavior that regulate activity-dependent BDNF secretion and/or potentiate TrkB receptor signaling would therefore be of considerable interest. In this study, we show in the adult mouse hippocampus that expression of the granin family gene Vgf and secretion of its C-terminal VGF-derived peptide TLQP-62 are required for fear memory formation. We found that hippocampal VGF expression and TLQP-62 levels were transiently induced after fear memory training and that sequestering secreted TLQP-62 peptide in the hippocampus immediately after training impaired memory formation. Reduced VGF expression was found to impair learning-evoked Rac1 induction and phosphorylation of the synaptic plasticity markers cofilin and synapsin in the adult mouse hippocampus. Moreover, TLQP-62 induced acute, transient activation of the TrkB receptor and subsequent CREB phosphorylation in hippocampal slice preparations and its administration immediately after training enhanced long-term memory formation. A critical role of BDNF-TrkB signaling as a downstream effector in VGF/TLQP-62-mediated memory consolidation was further revealed by posttraining activation of BDNF-TrkB signaling, which rescued impaired fear memory resulting from hippocampal administration of anti-VGF antibodies or germline VGF ablation in mice. We propose that VGF is a critical component of a positive BDNF-TrkB regulatory loop and, upon its induced expression by memory training, the TLQP-62 peptide rapidly reinforces BDNF-TrkB signaling, regulating hippocampal memory consolidation.
  
  
  CONCLUSIONS
  Identification of the cellular and molecular mechanisms that regulate long-term memory formation and storage may provide alternative treatment modalities for degenerative and neuropsychiatric memory disorders. The neurotrophin BDNF plays a prominent role in cognitive function, and rapidly and robustly induces expression of VGF, a secreted neuronal peptide precursor. VGF knock-out mice have impaired fear and spatial memory. Our study shows that VGF and VGF-derived peptide TLQP-62 are transiently induced after fear memory training, leading to increased BDNF/TrkB signaling, and that sequestration of hippocampal TLQP-62 immediately after training impairs memory formation. We propose that TLQP-62 is a critical component of a positive regulatory loop that is induced by memory training, rapidly reinforces BDNF-TrkB signaling, and is required for hippocampal memory consolidation.
authors.affiliation: Department of Neuroscience.
authors.forename: Wei-Jye
authors.initials: WJ
authors.lastname: Lin
authors.affiliation: Department of Neuroscience, Graduate School of Biomedical Sciences, and.
authors.forename: Cheng
authors.identifier: http://orcid.org/0000-0003-4583-3295
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Department of Neuroscience, Graduate School of Biomedical Sciences, and.
authors.forename: Masato
authors.initials: M
authors.lastname: Sadahiro
authors.affiliation: Department of Psychiatry, Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Ozlem
authors.initials: O
authors.lastname: Bozdagi
authors.affiliation: Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: Lucy
authors.initials: L
authors.lastname: Vulchanova
authors.affiliation: Center for Neural Science, New York University, New York, New York 10003, and.
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Alberini
authors.affiliation: Department of Neuroscience, Department of Geriatrics, Friedman Brain Institute, stephen.salton@mssm.edu.
authors.forename: Stephen R
authors.identifier: http://orcid.org/0000-0003-4087-8427
authors.initials: SR
authors.lastname: Salton
mesh_terms: D000818:Animals; D001362:Avoidance Learning; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D003213:Conditioning, Psychological / Q000502:physiology; D015536:Down-Regulation / Q000235:genetics; D020536:Enzyme Activators / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D044950:Flavanones / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009414:Nerve Growth Factors; D009474:Neurons / Q000502:physiology; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000008:administration & dosage* / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D020813:Receptor, trkB / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C478869:7,8-dihydroxyflavanone; D019208:Brain-Derived Neurotrophic Factor; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D044950:Flavanones; D009414:Nerve Growth Factors; D009479:Neuropeptides; D010455:Peptides; C000593377:TLQP62 peptide; C512697:Vgf protein, mouse; D049452:Green Fluorescent Proteins; D020813:Receptor, trkB
keywords: BDNF; Rac1; TLQP-62; TrkB; VGF; memory