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Antidepressant Effects of TrkB Ligands on Depression-Like Behavior and Dendritic Changes in Mice After Inflammation

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Antidepressant Effects of TrkB Ligands on Depression-Like Behavior and Dendritic Changes in Mice After Inflammation

Ji-chun Zhang et al. Int J Neuropsychopharmacol.

Abstract

Background: Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), signaling represent potential therapeutic targets for major depressive disorder. The purpose of this study is to examine whether TrkB ligands show antidepressant effects in an inflammation-induced model of depression.

Methods: In this study, we examined the effects of TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) and TrkB antagonist ANA-12 on depression-like behavior and morphological changes in mice previously exposed to lipopolysaccharide (LPS). Protein levels of BDNF, phospho-TrkB (p-TrkB), and TrkB in the brain regions were also examined.

Results: LPS caused a reduction of BDNF in the CA3 and dentate gyrus (DG) of the hippocampus and prefrontal cortex (PFC), whereas LPS increased BDNF in the nucleus accumbens (NAc). Dexamethason suppression tests showed hyperactivity of the hypothalamic-pituitary-adrenal axis in LPS-treated mice. Intraperitoneal (i.p.) administration of 7,8-DHF showed antidepressant effects on LPS-induced depression-like behavior, and i.p. pretreatment with ANA-12 blocked its antidepressant effects. Surprisingly, ANA-12 alone showed antidepressant-like effects on LPS-induced depression-like behavior. Furthermore, bilateral infusion of ANA-12 into the NAc showed antidepressant effects. Moreover, LPS caused a reduction of spine density in the CA3, DG, and PFC, whereas LPS increased spine density in the NAc. Interestingly, 7,8-DHF significantly attenuated LPS-induced reduction of p-TrkB and spine densities in the CA3, DG, and PFC, whereas ANA-12 significantly attenuated LPS-induced increases of p-TrkB and spine density in the NAc.

Conclusions: The results suggest that LPS-induced inflammation may cause depression-like behavior by altering BDNF and spine density in the CA3, DG, PFC, and NAc, which may be involved in the antidepressant effects of 7,8-DHF and ANA-12, respectively.

Keywords: BDNF-TrkB signaling; hippocampus; inflammation; nucleus accumbens; prefrontal cortex.

Figures

Figure 1.
Figure 1.
BDNF protein in the brains of control and LPS-treated mice. (A): The schedule of treatment. (B): Brain regions (CA1, CA3, DG, PFC, NAc) for Western blot analysis of BDNF. (C): Western blot analysis of BDNF in the CA1, CA3, and DG of the hippocampus, the PFC, and the NAc. The value was expressed as a percentage of that of saline-treated mice. Values represent the mean ± standard error of the mean (SEM; n = 6). *p < 0.05 compared with saline treated groups (student’s t-test). (D and E): Dexamethasome (DEX) suppression test. (D): The schedule of treatment. (E): Blood sample was collected 6 hours after injection of DEX, and serum corticosterone was measured by ELISA. Data represent mean ± SEM (n = 11–12 mice per group). *p < 0.05 compared with saline-treated groups (student’s t-test). LPS: lipopolysaccharide; DG: dentate gyrus; PFC: prefrontal cortex; NAc: nucleus accumbens.
Figure 2.
Figure 2.
Effects of 7,8-DHF and 5,7-DHF on LPS-induced depression-like behavior. (A) The schedule of treatment and behavioral evaluations. (B) Locomotion, (C) TST, and (D) FST tests. Values represent the mean ± standard error of the mean (n = 8–11). *p < 0.05, **p < 0.01, ***p < 0.001 compared with the vehicle + LPS group. N.S.: not significant. 7,8-DHF: 7,8-dihydroxyflavone; 5,7-DHF: 5,7-dihydroxyflavone; LPS: lipopolysaccharide; TST: tail suspension test; FST: forced swimming test.
Figure 3.
Figure 3.
Role of TrkB and mTORC1 in the antidepressant action of 7,8-DHF and ANA-12 on LPS-induced depression-like behavior. (A–C) The schedule of treatment and behavioral evaluations. (D) Locomotion, (E) TST, and (F) FST tests. Values represent the mean ± standard error of the mean (SEM). n = 8–10 for D, E, and F. **p < 0.01, ***p < 0.001 compared with the LPS + vehicle group. ## p < 0.01 compared with the LPS + 7,8-DHF + ANA-12 group. N.S.: not significant. (G) TST and (H) FST. Bilateral infusion of ANA-12 into the NAc significantly attenuated the increase of immobility time of LPS-treated mice. Values represent the mean ± SEM. n = 7 for (G) and (H). *p < 0.05, **p < 0.01 compared with the LPS + vehicle group. (I): TST, (J): FST. I.c.v. infusion of rapamycin significantly blocked the decrease of immobility time of LPS-treated mice by 7,8-DHF. In contrast, i.c.v. infusion of rapamycin did not affect the decrease of immobility time of LPS-treated mice by ANA-12. Values represent the mean ± SEM (n = 8 – 10). **p < 0.01, ***p < 0.001 compared with the LPS + vehicle group. ## p < 0.01 compared with the LPS + 7,8-DHF group. N.S.: not significant. TrkB: tropomyosin-receptor-kinase B; mTORC1: mammalian target of rapamycin complex 1; 7,8-DHF:7,8-dihydroxyflavone; TST: tail suspension test; FST: forced swimming test; NAc: nucleus accumbens; i.c.v.: intracerebroventricular.
Figure 4.
Figure 4.
Effects of 7,8-DHF and ANA-12 on LPS-induced changes in phosphorylation of TrkB in the mouse brain. (A): The schedule of treatment. (B): Western blot of p-TrkB protein in the mouse brain. (C): Western blot of total TrkB protein in the mouse brain. The value was expressed as a percentage of that of saline-treated mice. Values represent the mean ± standard error of the mean (n = 5–6). *p < 0.05, **p < 0.01, as compared with the LPS + vehicle group. # p < 0.05, ## p < 0.01 as compared with the LPS + 7,8-DHF group. N.S.: not significant. 7,8-DHF: 7,8-dihydroxyflavone; LPS: lipopolysaccharide; TrkB: tropomyosin-receptor-kinase B; p-TrkB: phospho-TrkB.
Figure 5.
Figure 5.
Effects of 7,8-DHF and ANA-12 on LPS-induced changes in spine density within mouse brain. (A): The schedule of treatment. (B): Representative photomicrographs of Golgi-Cox stained pyramidal neurons in the CA1, CA3, and DG of the hippocampus from animals of each group. Scale bar = 10 µm. (C): Values represent the mean ± standard error of the mean (SEM; n = 6). (D): Representative photomicrographs of Golgi-Cox stained pyramidal neurons in the PFC from animals of each group. Scale bar = 10 µm. (F): Values represent the mean ± SEM (n = 6). (E): Representative photomicrographs of Golgi-Cox stained pyramidal neurons in the NAc-shell and NAc-core from animals of each group. Scale bar = 10 µm. (G): Values represent the mean ± SEM (n = 6). *p < 0.05,**p < 0.01, ***p < 0.001 as compared with the LPS + vehicle group. 7,8-DHF: 7,8-dihydroxyflavone; LPS: lipopolysaccharide; DG: dentate gyrus; PFC: prefrontal cortex; NAc: nucleus accumbens.

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