Single fluoxetine treatment before but not after stress prevents stress-induced hippocampal long-term depression and spatial memory retrieval impairment in rats

Abstract

A growing body of evidence has shown that chronic treatment with fluoxetine, a widely prescribed medication for treatment of depression, can affect synaptic plasticity in the adult central nervous system. However, it is not well understood whether acute fluoxetine influences synaptic plasticity, especially on hippocampal CA1 long-term depression (LTD), and if so, whether it subsequently impacts hippocampal-dependent spatial memory. Here, we reported that LTD facilitated by elevated-platform stress in hippocampal slices was completely prevented by fluoxetine administration (10 mg/kg, i.p.) 30 min before stress. The LTD was not, however, significantly inhibited by fluoxetine administration immediately after stress. Similarly, fluoxetine incubation (10 μM) during electrophysiological recordings also displayed no influence on the stress-facilitated LTD. In addition, behavioral results showed that a single fluoxetine treatment 30 min before but not after acute stress fully reversed the impairment of spatial memory retrieval in the Morris water maze paradigm. Taken together, these results suggest that acute fluoxetine treatment only before, but not after stress, can prevent hippocampal CA1 LTD and spatial memory retrieval impairment caused by behavioral stress in adult animals.

Figure 1. A single injection of fluoxetine before elevated-platform stress prevents stress-facilitated hippocampal CA1 LTD.

(A) Classical LFS (1 Hz for 15 min) failed to induce LTD in non-stressed control rats. (B) Stress enabled LFS to induce a stable LTD in saline-treated rats. (C) Fluoxetine (10 mg/kg, i.p.) itself had no effect on LTD induction in non-stressed rats. (D) Fluoxetine injection 30 min before stress fully prevented stress-facilitated hippocampal LTD. (E) The bar graph summarized the average percentage change of fEPSP amplitude before and 55 min after HFS. Representative traces are shown on the right. **p < 0.01, post hoc Turkey’s test after ANOVA (F_{(3, 20)} = 7.705; p = 0.001).

Figure 2. A single injection of fluoxetine immediately after elevated-platform stress fails to prevent stress-facilitated hippocampal CA1 LTD.

(A) LFS failed to induce hippocampal LTD in non-stressed control. (B) Stress enabled LFS to induce a stable LTD in saline-treated rats. (C) Fluoxetine (10 mg/kg, i.p.) itself had no effect on LTD induction in non-stressed rats. (D) Fluoxetine injection immediately after stress failed to prevent stress-facilitated hippocampal LTD. (E) The bar graph summarized the average percentage change of fEPSP amplitude before and 55 min after HFS. Representative traces are shown on the right. **p < 0.01, post hoc Turkey’s test after ANOVA (F_{(3, 21)} = 12.661; p < 0.001).

Figure 3. Bath application of fluoxetine during fEPSP recording fails to prevent stress-facilitated hippocampal CA1 LTD.

(A) LFS failed to induce hippocampal LTD in non-stressed control. (B) Stress enabled LFS to induce a stable LTD. (C) Fluoxetine (10 μM) itself had no effect on LTD induction in non-stressed rats. (D) Bath application of fluoxetine failed to prevent stress-facilitated hippocampal LTD. (E) The bar graph summarized the average percentage change of fEPSP amplitude before and 55 min after HFS. Representative traces are shown on the right. *p < 0.05, **p < 0.01, post hoc Turkey’s test after ANOVA (F_{(3, 19)} = 9.954; p < 0.001).

Figure 4. A single injection of fluoxetine before but not after stress reverses the impairment of spatial memory retrieval.

(A) Plots displayed the average escape latencies of rats for each training day (day 1–6). (B) Histograms showed retrieval-test performance of rats from different treatment groups on day 7. Fluoxetine treatment 30 min before but not after stress dramatically rescued the deficit of spatial memory caused by stress, as reflected by spending longer time in the target quadrant where the hidden platform is located during training. *p < 0.05, **p < 0.01, post hoc Turkey’s test after ANOVA (F_{(3, 36)} = 5.734; p = 0.003). (C) Histograms summarized the effect of fluoxetine treatment before or after stress on retrieval-test performance, as reflected by hidden-platform crossings. *p < 0.05, **p < 0.01, post hoc Turkey’s test after ANOVA (F_{(3, 36)} = 10.652; p < 0.001). (D) Histograms summarized the effect of fluoxetine treatment before or after stress on retrieval-test performance, as reflected by latency of first platform crossing. *p < 0.05, **p < 0.01, post hoc Turkey’s test after ANOVA (F_{(3, 36)} = 9.602; p < 0.001).