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PI3K/AKT/mTOR signaling-mediated neuropeptide VGF in the hippocampus of mice is involved in the rapid onset antidepressant-like effects of GLYX-13.

Lu Y, Wang C, Xue Z, Li C, Zhang J, Zhao X, Liu A, Wang Q, Zhou W - Int. J. Neuropsychopharmacol. (2014)

Bottom Line: Further, Vgf knockdown in hippocampus of mice significantly blocked the rapid-acting antidepressant-like effects and upregulation on phosphatidylinositol 3-kinase/AKT/mTOR/VGF signaling of GLYX-13.Moreover, intra-hippocampus infusion of LY294002 significantly abolished the antidepressant-like effects and upregulation on phosphatidylinositol 3-kinase/AKT/mTOR/VGF signaling of GLYX-13.Our results suggest that phosphatidylinositol 3-kinase/AKT/mTOR signaling-mediated VGF in hippocampus may be involved in the antidepressant-like effects of GLYX-13.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, and Provincial Key Laboratory of Pathophysiology in Ningbo University School of Medicine, Ningbo, Zhejiang, PR China.

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Antidepressant-like effect of acute GLYX-13 treatment in mice. (a) Protocol for experiments using the open field test (OFT) and forced swim test (FST). The OFT was conducted 30 minutes after a single injection of vehicle, GLYX-13 (0.5, 5, and 10mg/kg, i.p.), or Desipramine (Des) (10mg/kg, i.p.). The FST was performed 30 minutes after the OFT. (b) Acute GLYX-13 (5 and 10mg/kg, i.p.) treatment significantly decreased immobility time in the FST. (c) Acute GLYX-13 (0.5, 5, and 10mg/kg, i.p.) treatment had no effects on locomotor activity, reflected by the line crossing (left) and rearing (right) in mice. The data are expressed as mean±SEM (n=9 per group). **P<.01, compared with vehicle-treated group.
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Figure 1: Antidepressant-like effect of acute GLYX-13 treatment in mice. (a) Protocol for experiments using the open field test (OFT) and forced swim test (FST). The OFT was conducted 30 minutes after a single injection of vehicle, GLYX-13 (0.5, 5, and 10mg/kg, i.p.), or Desipramine (Des) (10mg/kg, i.p.). The FST was performed 30 minutes after the OFT. (b) Acute GLYX-13 (5 and 10mg/kg, i.p.) treatment significantly decreased immobility time in the FST. (c) Acute GLYX-13 (0.5, 5, and 10mg/kg, i.p.) treatment had no effects on locomotor activity, reflected by the line crossing (left) and rearing (right) in mice. The data are expressed as mean±SEM (n=9 per group). **P<.01, compared with vehicle-treated group.

Mentions: Five sets of experiments were conducted. The first set was performed to assess the fast-acting antidepressant-like effects of acute GLYX-13 administration (Figure 1a). The second set of experiments was to investigate whether 21-day CUMS alters VGF and PI3K/AKT/mTOR signaling in the hippocampus of mice and to determine whether acute treatment of GLYX-13 (0.5, 5, and 10mg/kg, i.p.) reverses the depressive-like behaviors induced by CUMS in mice (Figure 2a). The third set was to demonstrate whether knock down of VGF in hippocampus by Vgf-shRNA-lentivirus blocks the antidepressant-like action of GLYX-13 (10mg/kg, i.p.) (Figure 4a). Lentiviral vectors containing NS-shRNA or Vgf-shRNA-lentivirus (5×107 TU/μL, 1 μL/side) were infused at a rate of 0.2 μL/min with an infusion pump, and the cannulas were left in place for 60 additional seconds to avoid back flow. The fourth set of experiments was to investigate whether i.h. infusion of LY294002 (10 nmol/side), a specific PI3K inhibitor, 30 minutes prior to the administration of GLYX-13 (10mg/kg, i.p.) significantly blocks the antidepressant-like behaviors in the open field test (OFT) (Figure 6a). The fifth set of experiments was to investigate whether i.h. infusions of NBQX (2 μg/side), a AMPA receptor inhibitor (NBQX), or mTOR inhibitor (rapamycin) 30 minutes prior to the administration of GLYX-13 (10mg/kg, i.p.) blocks the antidepressant-like behaviors of GLYX-13 (Figure 8a, e).


PI3K/AKT/mTOR signaling-mediated neuropeptide VGF in the hippocampus of mice is involved in the rapid onset antidepressant-like effects of GLYX-13.

Lu Y, Wang C, Xue Z, Li C, Zhang J, Zhao X, Liu A, Wang Q, Zhou W - Int. J. Neuropsychopharmacol. (2014)

Antidepressant-like effect of acute GLYX-13 treatment in mice. (a) Protocol for experiments using the open field test (OFT) and forced swim test (FST). The OFT was conducted 30 minutes after a single injection of vehicle, GLYX-13 (0.5, 5, and 10mg/kg, i.p.), or Desipramine (Des) (10mg/kg, i.p.). The FST was performed 30 minutes after the OFT. (b) Acute GLYX-13 (5 and 10mg/kg, i.p.) treatment significantly decreased immobility time in the FST. (c) Acute GLYX-13 (0.5, 5, and 10mg/kg, i.p.) treatment had no effects on locomotor activity, reflected by the line crossing (left) and rearing (right) in mice. The data are expressed as mean±SEM (n=9 per group). **P<.01, compared with vehicle-treated group.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License 1 - License 2
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Figure 1: Antidepressant-like effect of acute GLYX-13 treatment in mice. (a) Protocol for experiments using the open field test (OFT) and forced swim test (FST). The OFT was conducted 30 minutes after a single injection of vehicle, GLYX-13 (0.5, 5, and 10mg/kg, i.p.), or Desipramine (Des) (10mg/kg, i.p.). The FST was performed 30 minutes after the OFT. (b) Acute GLYX-13 (5 and 10mg/kg, i.p.) treatment significantly decreased immobility time in the FST. (c) Acute GLYX-13 (0.5, 5, and 10mg/kg, i.p.) treatment had no effects on locomotor activity, reflected by the line crossing (left) and rearing (right) in mice. The data are expressed as mean±SEM (n=9 per group). **P<.01, compared with vehicle-treated group.
Mentions: Five sets of experiments were conducted. The first set was performed to assess the fast-acting antidepressant-like effects of acute GLYX-13 administration (Figure 1a). The second set of experiments was to investigate whether 21-day CUMS alters VGF and PI3K/AKT/mTOR signaling in the hippocampus of mice and to determine whether acute treatment of GLYX-13 (0.5, 5, and 10mg/kg, i.p.) reverses the depressive-like behaviors induced by CUMS in mice (Figure 2a). The third set was to demonstrate whether knock down of VGF in hippocampus by Vgf-shRNA-lentivirus blocks the antidepressant-like action of GLYX-13 (10mg/kg, i.p.) (Figure 4a). Lentiviral vectors containing NS-shRNA or Vgf-shRNA-lentivirus (5×107 TU/μL, 1 μL/side) were infused at a rate of 0.2 μL/min with an infusion pump, and the cannulas were left in place for 60 additional seconds to avoid back flow. The fourth set of experiments was to investigate whether i.h. infusion of LY294002 (10 nmol/side), a specific PI3K inhibitor, 30 minutes prior to the administration of GLYX-13 (10mg/kg, i.p.) significantly blocks the antidepressant-like behaviors in the open field test (OFT) (Figure 6a). The fifth set of experiments was to investigate whether i.h. infusions of NBQX (2 μg/side), a AMPA receptor inhibitor (NBQX), or mTOR inhibitor (rapamycin) 30 minutes prior to the administration of GLYX-13 (10mg/kg, i.p.) blocks the antidepressant-like behaviors of GLYX-13 (Figure 8a, e).

Bottom Line: Further, Vgf knockdown in hippocampus of mice significantly blocked the rapid-acting antidepressant-like effects and upregulation on phosphatidylinositol 3-kinase/AKT/mTOR/VGF signaling of GLYX-13.Moreover, intra-hippocampus infusion of LY294002 significantly abolished the antidepressant-like effects and upregulation on phosphatidylinositol 3-kinase/AKT/mTOR/VGF signaling of GLYX-13.Our results suggest that phosphatidylinositol 3-kinase/AKT/mTOR signaling-mediated VGF in hippocampus may be involved in the antidepressant-like effects of GLYX-13.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, and Provincial Key Laboratory of Pathophysiology in Ningbo University School of Medicine, Ningbo, Zhejiang, PR China.

Show MeSH
Related in: MedlinePlus