TY - JOUR
T1 - VGF and its C-terminal peptide TLQP-62 in ventromedial prefrontal cortex regulate depression-related behaviors and the response to ketamine
AU - Jiang, Cheng
AU - Lin, Wei Jye
AU - Labonté, Benoit
AU - Tamminga, Carol A.
AU - Turecki, Gustavo
AU - Nestler, Eric J.
AU - Russo, Scott J.
AU - Salton, Stephen R.
N1 - Funding Information:
Supported in part by NIH grants MH086499 (SRS), MH083496 (SRS), pilot grant on P50AT008661 (SRS; PI G.M. Pasinetti); Hope for Depression Research Foundation (SRS); Brain and Behavior Research Foundation (SRS); BrightFocus Foundation (SRS). The authors report no biomedical financial interests or potential conflicts of interest.
Publisher Copyright:
© 2018, American College of Neuropsychopharmacology.
PY - 2019/4/1
Y1 - 2019/4/1
N2 - 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 IP 3 -mediated Ca 2+ release, or SKF96365, an inhibitor of store-operated and TRPC channel-mediated Ca 2+ 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.
AB - 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 IP 3 -mediated Ca 2+ release, or SKF96365, an inhibitor of store-operated and TRPC channel-mediated Ca 2+ 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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U2 - 10.1038/s41386-018-0277-4
DO - 10.1038/s41386-018-0277-4
M3 - Article
C2 - 30504797
AN - SCOPUS:85057617541
SN - 0893-133X
VL - 44
SP - 971
EP - 981
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
IS - 5
ER -