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

Masanori Nomoto,Hatsune Enomoto,Shizuka Kobayashi,Koji Mitsuda,Kaori Saito,Toshiya Manabe,Ayako M Watabe,Shusaku Uchida,Yohei Takeda,Satoshi Kida,Shoichi Masushige,Tesu Choi

doi:10.1186/1756-6606-5-8

Abstract

BackgroundRetinoid signaling pathways mediated by retinoic acid receptor (RAR)/retinoid × receptor (RXR)-mediated transcription play critical roles in hippocampal synaptic plasticity. Furthermore, recent studies have shown that treatment with retinoic acid alleviates age-related deficits in hippocampal long-term potentiation (LTP) and memory performance and, furthermore, memory deficits in a transgenic mouse model of Alzheimer's disease. However, the roles of the RAR/RXR signaling pathway in learning and memory at the behavioral level have still not been well characterized in the adult brain. We here show essential roles for RAR/RXR in hippocampus-dependent learning and memory. In the current study, we generated transgenic mice in which the expression of dominant-negative RAR (dnRAR) could be induced in the mature brain using a tetracycline-dependent transcription factor and examined the effects of RAR/RXR loss.ResultsThe 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.ConclusionsFrom 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.

Highlights

Retinoid signaling pathways mediated by retinoic acid receptor (RAR)/retinoid × receptor (RXR)mediated transcription play critical roles in hippocampal synaptic plasticity
Vitamin A-deficient mice display impaired hippocampal long-term potentiation (LTP) that is rescued by treatment with Retinoic acids (RAs) [19,20]. These findings strongly suggest that the RAR/RXR signaling pathway plays critical roles in hippocampal LTP and long-term depression (LTD)
To understand the roles of the RAR/RXR signaling pathway in learning and memory and synaptic plasticity, we examined the effects of impaired RAR/RXR function in the forebrain

Summary

Introduction

Retinoid signaling pathways mediated by retinoic acid receptor (RAR)/retinoid × receptor (RXR)mediated transcription play critical roles in hippocampal synaptic plasticity. Recent studies have shown that treatment with retinoic acid alleviates age-related deficits in hippocampal long-term potentiation (LTP) and memory performance and, memory deficits in a transgenic mouse model of Alzheimer’s disease. 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]. Recent studies using mice have shown that age-related memory deficits are associated with the hypo-function of vitamin A-RA signaling pathways and these deficits are restored by treatment with RA or supplementation of vitamin A [16,17]

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