All-trans retinoic acid (ATRA), the endogenous active derivative of vitamin A, plays a role in cell growth, neural differentiation, and synaptic plasticity during development and operates exclusively by regulating gene transcription. A synthetic retinoid used to treat acne, 13- cis-retinoic acid (13- cis-RA isotretinoin), has been linked to depression and suicide, since its approval in 1982. Excessive consumption of vitamin A (hypervitaminosis A) has long been known to cause adverse psychiatric events. Retinoic signaling is reportedly linked with the development of the central nervous system (CNS) and the pathogenesis of depression in adults. Synapse differentiation-inducing gene protein 1 These results might constitute a novel target underlying ATRA-induced anxiety- and depression-like behavior. Moreover, DLG2 was correlated with anxiety-like behavior and SynDIG1 was correlated with depression-like behavior. To summarize, ATRA administration induced anxiety- and depression-like behavior accompanied by a decreased expression of DLG2 and an increased expression of SynDIG1. Retinoic acid receptor γ mRNA was significantly positively correlated with DLG2 and negatively correlated with SynDIG1. There was a negative correlation between SynDIG1 mRNA levels and mobility time in the forced swimming test. Increased SynDIG1 mRNA levels were observed. mRNA levels were positively correlated with central area duration and distance in the open-field test. In the hippocampus, DLG2 mRNA was significantly decreased by ATRA. Three different doses of ATRA were injected into young mice and 10 mg/kg ATRA was found to induce depression-like behavior. We examined two genes associated with synaptic function, discs large homolog 2 (DLG2), and synapse differentiation-inducing gene protein 1 (SynDIG1) in terms of hippocampal expression and correlation with behavior. The hippocampus seems to be a major target of retinoids, and abnormal synaptic plasticity of the hippocampus is involved in depression. Although it has been shown that all-trans retinoic acid (ATRA) administration induces behavioral changes, further insight into how ATRA is involved is lacking. Clinical reports suggest a potential link between excess retinoids and development of depression.
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