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Neuropsychopharmacology. 2018 Nov 20. doi: 10.1038/s41386-018-0277-4. [Epub ahead of print]

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

Author information

1
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
2
RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangdong, 510120, Guangzhou, China.
3
Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangdong, Guangzhou, China.
4
Department of Neuroscience and Psychiatry, Faculty of Medicine, Laval University, 2601 Chemin de la Canardière, Québec, QC, G1J 2G3, Canada.
5
Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, 75235, USA.
6
Department of Psychiatry, McGill University, Montréal, Québec, Canada.
7
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
8
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. stephen.salton@mssm.edu.
9
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. stephen.salton@mssm.edu.
10
Department of Geriatrics, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. stephen.salton@mssm.edu.

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.

PMID:
30504797
DOI:
10.1038/s41386-018-0277-4

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