Research ArticleNEUROSCIENCE

HSP105 prevents depression-like behavior by increasing hippocampal brain-derived neurotrophic factor levels in mice

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Science Advances  31 May 2017:
Vol. 3, no. 5, e1603014
DOI: 10.1126/sciadv.1603014
  • Fig. 1 Stress-induced HSP mRNA level changes in the hippocampus.

    Quantitative reverse transcription PCR analysis showing the expression levels of HSP25, HSP60, HSP72, and HSP105 (n = 4 to 5 animals per group). Each bar indicates the mean ± SEM. Statistically different groups are indicated by letters.

  • Fig. 2 Effects of GGA on HSP expression in the hippocampus.

    The level of HSP mRNA in the hippocampus was detected by quantitative reverse transcription PCR. HSP25 mRNA (A), HSP60 mRNA (B), HSP72 mRNA (C), HSP105 mRNA (D), and HSP105 protein (E) (n = 5 to 6 animals per group). Each bar indicates the mean ± SEM, with significant differences as inserts on the chart (P < 0.05). Groups were first tested by two-way analysis of variance (ANOVA). Then, if a statistical interaction was observed between factors, comparison of all four groups was performed by one-way ANOVA with Tukey’s post hoc test. Statistically different groups are indicated by letters. n.s., not significant; VEH, vehicle; GAPDH, glyceraldehyde-3-phosphate dehydrogenase.

  • Fig. 3 GGA administration rescues depression-like behavior and hippocampal proliferation.

    (A) Interaction rate in the interaction test. (B) Immobility times in the forced swim test. (C) Immobility times in the tail suspension test. Sucrose preferences (D) and total fluid intake (E) in the sucrose preference test. (F) General behavior in the open-field test locomotor activity, rearing activity, or time spent in the center area (n = 4 to 5 animals per group). (G) Photomicrographs of the dentate gyrus showing representative DCX-positive cells. Scale bar, 100 μm. Arrows show immunopositive cells. Right: Number of DCX-positive cells. Each bar indicates the mean ± SEM, with significant differences shown as inserts on the chart (P < 0.05). Groups were first tested by two-way ANOVA. Then, if a statistical interaction was observed between factors, comparison of all four groups was performed by one-way ANOVA with Tukey’s post hoc test. Statistically different groups are indicated by letters.

  • Fig. 4 Effects of GGA administration on mRNA levels of neurotrophic factors in the stressed mouse hippocampus.

    Mice were administered vehicle or GGA orally. Quantitative reverse transcription PCR analysis showing the expression levels of (A) BDNF, (B) NGF, (C) CNTF, and (D) NT-3 (n = 5 animals per group). (E) Western blotting of BDNF protein expression in mouse hippocampus (n = 4 to 5 animals per group). Each bar indicates the mean ± SEM, with significant differences shown as inserts on the chart (P < 0.05). Groups were first tested by two-way ANOVA. Then, if a statistical interaction was observed between factors, comparison of all four groups was performed by one-way ANOVA with Tukey’s post hoc test. Statistically different groups are indicated by letters.

  • Fig. 5 The BDNF receptor inhibitor K252a suppresses GGA-induced antidepressant-like effects.

    (A) Social interaction rate in the interaction test. (B) Immobility times in the forced swim test. (C) Immobility times in the tail suspension test. (D) Sucrose preference and total fluid intake in the sucrose preference test. (E) No significant effect on general behavior, locomotor activity, rearing activity, or time spent in the center area in the open-field test (n = 5 animals per group). Each bar indicates the mean ± SEM, with significant differences shown as inserts on the chart (P < 0.05). Groups were first tested by two-way ANOVA. Then, if a statistical interaction was observed between factors, comparison of all four groups was performed by one-way ANOVA with Tukey’s post hoc test. Statistically different groups are indicated by letters.

  • Fig. 6 HSP105-siRNA in HT22 cells or stressed mouse brain decreased BDNF levels and abolished antidepressant effects.

    (A) Level of HSP105 mRNA in HT22 cells (ANOVA, F2,13 = 544.1, n = 5 to 6). (B) Level of BDNF mRNA in HT22 cells (ANOVA, F2,13 = 10.74, n = 5 to 6). (C) The level of HSP105 protein in the hippocampus was detected by Western blotting (n = 3). (D) Immobility times in the forced swim test (ANOVA, F2,11 = 6.03). (E) Immobility times in the tail suspension test (ANOVA, F2,11 = 15.02). (F) Social interaction rate in the interaction test (ANOVA, F2,11 = 5.00). (G) Sucrose preference and total fluid intake in the sucrose preference test. (H) Level of BDNF mRNA and protein in the mouse hippocampus (ANOVA, F2,11 = 4.54 and F2,12 = 5.41, respectively) (n = 4 to 5 animals per group). Each bar indicates the mean ± SEM. GGA + NTC, GGA with nontargeting control; GGA + HSP105-siRNA, GGA with HSP105-siRNA treatment. Statistically different groups are indicated by letters.

  • Table 1 Characteristics of study population over 5 years (2010–2015) in the FAERS database.
    Case with depression, n (%)Non-cases, n (%)
    Total49,839 (100)2,277,014 (100)
    Male15,353 (30.8)856,772 (37.6)
    Female34,486 (69.2)1,420,242 (62.4)
    Mean age (years)48.354.1
  • Table 2 Association of teprenone with depressive events in patient using peginterferon α-2a, peginterferon α-2b, or ribavirin. CI, confidence interval.
    Cases with
    depression, n
    Non-
    cases, n
    Reporting odds
    ratio (95% CI)
    Total (male and female)
      Teprenone not present162641,3481.82 (1.73–1.92)
      Teprenone present104031.13 (0.61–2.12)
    Male
      Teprenone not present90423,3932.23 (2.08–2.39)
      Teprenone present51961.42 (0.59–3.46)
    Female
      Teprenone not present72217,9551.67 (1.55–1.80)
      Teprenone present52070.99 (0.41–2.42)

Supplementary Materials

  • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/3/5/e1603014/DC1

    fig. S1. Effect of stress or GGA on mature neurons in the mouse hippocampus.

    fig. S2. Effect of stress or GGA on BDNF distribution in the mouse hippocampus.

    fig. S3. Effect of GGA or GGA + K252a on mouse behavior with nonstress conditioning.

    fig. S4. Effect of HSP105-siRNA on expression of HSP25, HSP60, and HSP72 in the nonstressed mouse hippocampus (n = 4 animals per group).

    fig. S5. Effect of GGA on phospho-CREB expression in the stressed mouse hippocampus (stress + VEH, n = 5; stress + GGA, n = 6 animals).

    table S1. Oligonucleotide sequences for real-time PCR amplification.

    table S2. A 2 × 2 table used for the calculation of ROR.

  • Supplementary Materials

    This PDF file includes:

    • fig. S1. Effect of stress or GGA on mature neurons in the mouse hippocampus.
    • fig. S2. Effect of stress or GGA on BDNF distribution in the mouse hippocampus.
    • fig. S3. Effect of GGA or GGA + K252a on mouse behavior with nonstress conditioning.
    • fig. S4. Effect of HSP105-siRNA on expression of HSP25, HSP60, and HSP72 in the nonstressed mouse hippocampus (n = 4 animals per group).
    • fig. S5. Effect of GGA on phospho-CREB expression in the stressed mouse hippocampus (stress + VEH, n = 5; stress + GGA, n = 6 animals).
    • table S1. Oligonucleotide sequences for real-time PCR amplification.
    • table S2. A 2 × 2 table used for the calculation of ROR.

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