Dysfunction of the RAR/RXR signaling pathway in the forebrain impairs hippocampal memory and synaptic plasticity

The expression of dnRAR in the forebrain down-regulated the expression of RARβ, a target gene of RAR/RXR, indicating that dnRAR mice exhibit dysfunction of the RAR/RXR signaling pathway. Similar with previous findings, dnRAR mice displayed impaired LTP and AMPA-mediated synaptic transmission in the hippocampus. More importantly, these mutant mice displayed impaired hippocampus-dependent social recognition and spatial memory. However, these deficits of LTP and memory performance were rescued by stronger conditioning stimulation and spaced training, respectively. Finally, we found that pharmacological blockade of RARα in the hippocampus impairs social recognition memory.From these observations, we concluded that the RAR/RXR signaling pathway greatly contributes to learning and memory, and LTP in the hippocampus in the adult brain.Retinoic acids (RAs) are biologically active metabolites of vitamin A, an essential nutrient factor [1-3]. Vitamin A-RA signaling pathways play essential roles in a wide range of biological functions such as reproduction, growth, differentiation, development, vision, and homeostasis of various tissues, including the brain [2,4].All-trans-RA and 9-cis-isomers of RA bind to their nuclear receptor, i.e., RA receptors (RARα, β, and γ) and retinoid × receptors (RXRα, β, and γ), which function as ligand-inducible transcription factors [4,5]. RA binding to RAR and RXR, respectively, forms a heterodimer of RAR/RXR or a homodimer of RXR/RXR and regulates the transcription of target genes by binding to retinoic acid responsive elements in their promoter regions, thereby regulating various biological phenomena [4,6].RAR and RXR, especially RARα are highly expressed in a wide range of central nervous system tissues including the mature brain [7,8]. Moreover, there is growing evidence that vitamin A-RA signaling pathways have an impact on higher brain function; furthermore, an impairment of these signaling pathways is implicated in the etiology of Alzheim