Chronic retinoic acid treatment induces affective disorders by impairing the synaptic plasticity of the hippocampus.

Background: More and more people are suffering from depression in modern society. It is believed that the development of depression results from alterations in synaptic transmission, especially in the hippocampus. Animal experiments and clinical studies have demonstrated that retinoids are essential components in hippocampal synaptic plasticity, and they have a close relationship with depression. However, it is still unclear how excessive retinoic acid (RA) causes depression and what synaptic and molecular mechanisms underlie it.

Methods: Behavioral, electrophysiological, and molecular approaches were employed to characterize the effects of RA on depression and synaptic plasticity. RA was continuously administered intracerebroventricularly through an osmotic pump.

Results: RA treatment induced depression-like behaviors, as evidenced by decreased sucrose preference and increased immobile duration in both the forced swim test and the tail suspension test. RA administration also induced anxiety-like behaviors, indicated by decreased duration in the open arms of the elevated plus maze and the central of the open field. RA treatment decreased the neuronal excitability of the hippocampus either by changing the excitatory/inhibitory receptor balance or by promoting the synthesis of inhibitory neurotransmitters. Moreover, long-term potentiation was decreased in both the excitatory postsynaptic potential and the population spike in RA-treated rats, presumably a consequence of the reduced glur1 transcript level.

Limitations: The mechanism of how excess RA affects the hippocampal gene expression and synaptic plasticity requires further study.

Conclusions: RA treatment can induce depression-like behavior in rats and impair hippocampal plasticity. Thus, improving synaptic plasticity in the hippocampus may ameliorate the affective disorders caused by excessive RA.