TY - JOUR
T1 - Dysfunction of the RAR/RXR signaling pathway in the forebrain impairs hippocampal memory and synaptic plasticity
AU - Nomoto, Masanori
AU - Takeda, Yohei
AU - Uchida, Shusaku
AU - Mitsuda, Koji
AU - Enomoto, Hatsune
AU - Saito, Kaori
AU - Choi, Tesu
AU - Watabe, Ayako M.
AU - Kobayashi, Shizuka
AU - Masushige, Shoichi
AU - Manabe, Toshiya
AU - Kida, Satoshi
N1 - Funding Information:
S.K. was supported by Grant-in-Aids for Scientific Research (B) (23300120 and 20380078) and (C) (18580129), Grant-in-Aids for Scientific Research on Priority Areas -Molecular Brain Science-(18022038 and 22022039), High Technology Research and from the Ministry of Education, Culture, Sports, Science, and Technology, Japan, Core Research for Evolutional Science and Technology (CREST), Japan, a Research Grant for Nervous and Mental Disorders from the Ministry of Health, Labor, and Welfare, Japan, 4th Itsuu Laboratory Research Grant, Japan, The Sumitomo Foundation, Japan and the Takeda Science Foundation, Japan.
PY - 2012
Y1 - 2012
N2 - Background: Retinoid 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. Results: The expression of dnRAR in the forebrain down-regulated the expression of RAR, 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 RAR in the hippocampus impairs social recognition memory. Conclusions: 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.
AB - Background: Retinoid 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. Results: The expression of dnRAR in the forebrain down-regulated the expression of RAR, 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 RAR in the hippocampus impairs social recognition memory. Conclusions: 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.
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U2 - 10.1186/1756-6606-5-8
DO - 10.1186/1756-6606-5-8
M3 - Article
C2 - 22316320
AN - SCOPUS:84856602346
VL - 5
JO - Molecular Brain
JF - Molecular Brain
SN - 1756-6606
IS - 1
M1 - 8
ER -