VGF function in depression and antidepressant efficacy

C. Jiang, W. J. Lin, M. Sadahiro, B. Labonté, C. Menard, M. L. Pfau, C. A. Tamminga, G. Turecki, E. J. Nestler, S. J. Russo, S. R. Salton

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Brain-derived neurotrophic factor (BDNF) is a critical effector of depression-like behaviors and antidepressant responses. Here, we show that VGF (non-acronymic), which is robustly regulated by BDNF/TrkB signaling, is downregulated in hippocampus (male/female) and upregulated in nucleus accumbens (NAc) (male) in depressed human subjects and in mice subjected to chronic social defeat stress (CSDS). Adeno-associated virus (AAV)-Cre-mediated Vgf ablation in floxed VGF mice, in dorsal hippocampus (dHc) or NAc, led to pro-depressant or antidepressant behaviors, respectively, while dHc- or NAc-AAV-VGF overexpression induced opposite outcomes. Mice with reduced VGF levels in the germ line (Vgf+/−) or in dHc (AAV-Cre-injected floxed mice) showed increased susceptibility to CSDS and impaired responses to ketamine treatment in the forced swim test. Floxed mice with conditional pan-neuronal (Synapsin-Cre) but not those with forebrain (αCaMKII-Cre) Vgf ablation displayed increased susceptibility to subthreshold social defeat stress, suggesting that neuronal VGF, expressed in part in inhibitory interneurons, regulates depression-like behavior. Acute antibody-mediated sequestration of VGF-derived C-terminal peptides AQEE-30 and TLQP-62 in dHc induced pro-depressant effects. Conversely, dHc TLQP-62 infusion had rapid antidepressant efficacy, which was reduced in BDNF floxed mice injected in dHc with AAV-Cre, and in NBQX- and rapamycin-pretreated wild-type mice, these compounds blocking α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and mammalian target of rapamycin (mTOR) signaling, respectively. VGF is therefore a critical modulator of depression-like behaviors in dHc and NAc. In hippocampus, the antidepressant response to ketamine is associated with rapid VGF translation, is impaired by reduced VGF expression, and as previously reported, requires coincident, rapid BDNF translation and release.

Original languageEnglish (US)
Pages (from-to)1632-1642
Number of pages11
JournalMolecular Psychiatry
Volume23
Issue number7
DOIs
StatePublished - Jul 1 2018

Fingerprint

Antidepressive Agents
Hippocampus
Depression
Dependovirus
Brain-Derived Neurotrophic Factor
Nucleus Accumbens
Ketamine
Sirolimus
Synapsins
Calcium-Calmodulin-Dependent Protein Kinase Type 2
AMPA Receptors
Interneurons
Prosencephalon
Germ Cells
Down-Regulation
Peptides
Acids
Antibodies

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Jiang, C., Lin, W. J., Sadahiro, M., Labonté, B., Menard, C., Pfau, M. L., ... Salton, S. R. (2018). VGF function in depression and antidepressant efficacy. Molecular Psychiatry, 23(7), 1632-1642. https://doi.org/10.1038/mp.2017.233

VGF function in depression and antidepressant efficacy. / Jiang, C.; Lin, W. J.; Sadahiro, M.; Labonté, B.; Menard, C.; Pfau, M. L.; Tamminga, C. A.; Turecki, G.; Nestler, E. J.; Russo, S. J.; Salton, S. R.

In: Molecular Psychiatry, Vol. 23, No. 7, 01.07.2018, p. 1632-1642.

Research output: Contribution to journalArticle

Jiang, C, Lin, WJ, Sadahiro, M, Labonté, B, Menard, C, Pfau, ML, Tamminga, CA, Turecki, G, Nestler, EJ, Russo, SJ & Salton, SR 2018, 'VGF function in depression and antidepressant efficacy', Molecular Psychiatry, vol. 23, no. 7, pp. 1632-1642. https://doi.org/10.1038/mp.2017.233
Jiang C, Lin WJ, Sadahiro M, Labonté B, Menard C, Pfau ML et al. VGF function in depression and antidepressant efficacy. Molecular Psychiatry. 2018 Jul 1;23(7):1632-1642. https://doi.org/10.1038/mp.2017.233
Jiang, C. ; Lin, W. J. ; Sadahiro, M. ; Labonté, B. ; Menard, C. ; Pfau, M. L. ; Tamminga, C. A. ; Turecki, G. ; Nestler, E. J. ; Russo, S. J. ; Salton, S. R. / VGF function in depression and antidepressant efficacy. In: Molecular Psychiatry. 2018 ; Vol. 23, No. 7. pp. 1632-1642.
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