(R)-Ketamine Rapidly Ameliorates the Decreased Spine Density in the Medial Prefrontal Cortex and Hippocampus of Susceptible Mice After Chronic Social Defeat Stress

Abstract

Background: A recent study demonstrated that spine formation rates by ketamine in the prefrontal cortex (PFC) were not altered at 3-6 h following a single injection, but were markedly altered at 12-24 h. Here, we investigated the acute (3 h post-treatment) effects of (R)-ketamine in the decreased spine density in the medial PFC (mPFC) and hippocampus in susceptible mice after chronic social defeat stress (CSDS).

Methods: (R)-ketamine (10 mg/kg) or saline was administered intraperitoneally to CSDS-susceptible mice. Dendritic spine density in the mPFC and hippocampus was measured 3 h after a single injection.

Results: (R)-ketamine significantly ameliorated the decreased spine density in the prelimbic area of mPFC, Cornu Ammonis3, and dentate gyrus of the hippocampus of CSDS-susceptible mice.

Conclusions: This study suggests that (R)-ketamine rapidly ameliorates the decreased spine density in the mPFC and hippocampus of CSDS-susceptible mice, resulting in its rapid-acting antidepressant effects.

Keywords: (R)-ketamine; Rapid-acting antidepressant; dendritic spine density; hippocampus; medial prefrontal cortex.

Figure 1.

Schedule of CSDS, treatment, and brain collection. CSDS was performed from Day 1 to Day 10. A social interaction test was performed on Day 11 to select susceptible mice. On Day 12, saline (10 ml/kg) or (R)-ketamine (10 mg/kg) was administered i.p. to susceptible mice. Saline (10 ml/kg) was also administered i.p. to control (no CSDS) mice. Golgi-Cox staining in the control mice and CSDS-susceptible mice was performed 3 hours after a single administration of saline or (R)-ketamine. Abbreviations: CSDS, chronic social defeat stress; D, day; i.p., intraperitoneal.

Figure 2.

Rapid effects of (R)-ketamine on the decreased dendritic spine density in the prefrontal cortex and hippocampus in susceptible mice after CSDS. (A-E) Dendritic spine density in the PrL and IL regions of the mPFC, CA1, CA3, and DG of the hippocampus. The bar is 10 μm. (A) PrL region of mPFC (1-way ANOVA, F_2,21 = 4.825; P = 0.019). (B) IL region of mPFC (1-way ANOVA, F_2,21 = 0.027; P = 0.973). (C) CA1 of hippocampus (1-way ANOVA, F_2,21 = 0.019; P = 0.982). (D) CA3 of hippocampus (1-way ANOVA, F_2,21 = 8.144; P = 0.002). (E) DG of hippocampus (1-way ANOVA, F_2,21 = 14.070; P < 0.001). The values represent the mean ± standard error of the mean (n = 8/group). #P < 0.05, ##P < 0.01, and ###P < 0.001, compared with saline-treated CSDS-susceptible mice. Abbreviations: ANOVA, analysis of variance; CSDS, chronic social defeat stress; DG, dentate gyrus; IL, infralimbic; mPFC, medial prefrontal cortex; N.S., not significant; PrL, prelimbic; R-KT, (R)-ketamine.