VGF and its C-terminal peptide TLQP-62 in ventromedial prefrontal cortex regulate depression-related behaviors and the response to ketamine

Neuropsychopharmacology. 2019 Apr;44(5):971-981. doi: 10.1038/s41386-018-0277-4. Epub 2018 Nov 20.


Patients with major depressive disorder (MDD) often have structural and functional deficits in the ventromedial prefrontal cortex (vmPFC), but the underlying molecular pathways are incompletely understood. The neuropeptide precursor VGF (non-acronymic) plays a critical role in depression and antidepressant efficacy in hippocampus and nucleus accumbens, however its function in vmPFC has not been investigated. Here, we show that VGF levels were reduced in Brodmann area 25 (a portion of human vmPFC) of MDD patients and in mouse vmPFC following chronic restraint stress (CRS), and were increased by ketamine in mouse vmPFC. VGF overexpression in vmPFC prevented behavioral deficits induced by CRS, and VGF knockdown in vmPFC increased susceptibility to subchronic variable stress (SCVS) and reduced ketamine's antidepressant efficacy. Acute intra-vmPFC TLQP-62 infusion induced behavioral phenotypes that mimic those produced by antidepressant drug treatment. These antidepressant-like effects were sustained for 7 days and were abolished by local Bdnf gene ablation, or pretreatment with xestospongin C, an inhibitor of IP3-mediated Ca2+ release, or SKF96365, an inhibitor of store-operated and TRPC channel-mediated Ca2+ entry. In conclusion, VGF in the vmPFC regulates susceptibility to stress and the antidepressant response to ketamine. TLQP-62 infusion produces sustained antidepressant responses that require BDNF expression and calcium mobilization in vmPFC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents / administration & dosage
  • Antidepressive Agents / pharmacology*
  • Behavior, Animal / drug effects
  • Brain-Derived Neurotrophic Factor / metabolism
  • Depression / drug therapy*
  • Depression / etiology
  • Depression / metabolism*
  • Depressive Disorder, Major / metabolism*
  • Disease Models, Animal
  • Disease Susceptibility / metabolism
  • Female
  • Humans
  • Ketamine / administration & dosage
  • Ketamine / pharmacology*
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nerve Growth Factors / metabolism*
  • Neuropeptides / metabolism*
  • Peptides / administration & dosage
  • Peptides / pharmacology*
  • Prefrontal Cortex / drug effects*
  • Prefrontal Cortex / metabolism*
  • Stress, Psychological / complications


  • Antidepressive Agents
  • Brain-Derived Neurotrophic Factor
  • Nerve Growth Factors
  • Neuropeptides
  • Peptides
  • TLQP62 peptide
  • VGF protein, human
  • Vgf protein, mouse
  • Ketamine