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

Cheng Jiang, Wei Jye Lin, Benoit Labonté, Carol A Tamminga, Gustavo Turecki, Eric J. Nestler, Scott J. Russo, Stephen R. Salton

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
JournalNeuropsychopharmacology
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Ketamine
Prefrontal Cortex
Depression
Peptides
Antidepressive Agents
1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole
Major Depressive Disorder
Brain-Derived Neurotrophic Factor
Nucleus Accumbens
Neuropeptides
Hippocampus
Calcium
Phenotype

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

Cite this

VGF and its C-terminal peptide TLQP-62 in ventromedial prefrontal cortex regulate depression-related behaviors and the response to ketamine. / Jiang, Cheng; Lin, Wei Jye; Labonté, Benoit; Tamminga, Carol A; Turecki, Gustavo; Nestler, Eric J.; Russo, Scott J.; Salton, Stephen R.

In: Neuropsychopharmacology, 01.01.2018.

Research output: Contribution to journalArticle

Jiang, Cheng ; Lin, Wei Jye ; Labonté, Benoit ; Tamminga, Carol A ; Turecki, Gustavo ; Nestler, Eric J. ; Russo, Scott J. ; Salton, Stephen R. / VGF and its C-terminal peptide TLQP-62 in ventromedial prefrontal cortex regulate depression-related behaviors and the response to ketamine. In: Neuropsychopharmacology. 2018.
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abstract = "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.",
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