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

Nomoto M, Takeda Y, Uchida S, Mitsuda K, Enomoto H, Saito K, Choi T, Watabe AM, Kobayashi S, Masushige S, Manabe T, Kida S - Mol Brain (2012)

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Bioscience, Tokyo University of Agriculture, Tokyo, Japan.

ABSTRACT

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 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.

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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Impaired social recognition memory in dnRAR mice and its rescue by stronger training. (A) STM formed by training for 1.5 min (WT, n = 14; H06, n = 15). Recognition index (left panel). *p < 0.05, compared with WT. Investigation time (right panel). *p < 0.05, compared with training. (B) STM formed by training for 3 min (WT, n = 8; H06, n = 10). Recognition index (left panel). *p < 0.05, compared with WT. Investigation time (right panel). *p < 0.05, compared with training. (C) LTM formed by training for 3 min (WT, n = 28; OFF/ON, n = 26; OFF, n = 17). Recognition index (left panel). *p < 0.05, compared with the other groups. Investigation time (right panel). *p < 0.05, compared with training. (D) LTM formed by massed or spaced training (0 min: WT, n = 11; H06, n = 13; 10 min: WT, n = 12; H06, n = 11; 1 h: WT, n = 17; H06, n = 11). Recognition index (left panel). *p < 0.05, compared with the other groups. Investigation time (right panel). *p < 0.05, compared with the first exposure during training. (E) LTM formed by training for 3 min in WT (n = 11) and dnRAR H02 (n = 13) mice. Recognition index (left panel). *p < 0.05. Investigation time (right panel). *p < 0.05, compared with training. Error bars indicate SEM.
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Figure 3: Impaired social recognition memory in dnRAR mice and its rescue by stronger training. (A) STM formed by training for 1.5 min (WT, n = 14; H06, n = 15). Recognition index (left panel). *p < 0.05, compared with WT. Investigation time (right panel). *p < 0.05, compared with training. (B) STM formed by training for 3 min (WT, n = 8; H06, n = 10). Recognition index (left panel). *p < 0.05, compared with WT. Investigation time (right panel). *p < 0.05, compared with training. (C) LTM formed by training for 3 min (WT, n = 28; OFF/ON, n = 26; OFF, n = 17). Recognition index (left panel). *p < 0.05, compared with the other groups. Investigation time (right panel). *p < 0.05, compared with training. (D) LTM formed by massed or spaced training (0 min: WT, n = 11; H06, n = 13; 10 min: WT, n = 12; H06, n = 11; 1 h: WT, n = 17; H06, n = 11). Recognition index (left panel). *p < 0.05, compared with the other groups. Investigation time (right panel). *p < 0.05, compared with the first exposure during training. (E) LTM formed by training for 3 min in WT (n = 11) and dnRAR H02 (n = 13) mice. Recognition index (left panel). *p < 0.05. Investigation time (right panel). *p < 0.05, compared with training. Error bars indicate SEM.

Mentions: To investigate the effects of the impaired RAR/RXR signaling pathway on learning and memory, we performed a hippocampus-dependent social recognition memory task. This task measures the difference in the time taken to investigate a juvenile mouse by comparing between the first (training) and second (test) exposures to the mouse [32,33]. We first examined 2 h-short-term memory (STM; Figure 3A). Mice were exposed to a juvenile mouse for 1.5 min during the training and test sessions, which were performed 2 h apart. We measured the social investigation time of WT and OFF/ON-dnRAR H06 mice with the juvenile mouse during the training and test sessions and assessed the recognition index (i.e., the ratio of the social investigation time at the test relative to the training). One-way ANOVA with genotype (dnRAR and WT) revealed a significant effect of genotype (F(1,27) = 12.107, p < 0.05). The post hoc Newman-Keuls test revealed that dnRAR H06 mice showed a significantly worse recognition index than the WT mice (p < 0.05). Consistently, comparison of the social investigation time from the training and test sessions indicated that WT mice, but not OFF/ON-dnRAR H06 mice, displayed a significant decrease in social investigation time during the test compared to the training, indicating that WT mice formed STM, while OFF/ON-dnRAR H06 mice did not. These results indicated that OFF/ON-dnRAR H06 mice have impaired STM.


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

Nomoto M, Takeda Y, Uchida S, Mitsuda K, Enomoto H, Saito K, Choi T, Watabe AM, Kobayashi S, Masushige S, Manabe T, Kida S - Mol Brain (2012)

Impaired social recognition memory in dnRAR mice and its rescue by stronger training. (A) STM formed by training for 1.5 min (WT, n = 14; H06, n = 15). Recognition index (left panel). *p < 0.05, compared with WT. Investigation time (right panel). *p < 0.05, compared with training. (B) STM formed by training for 3 min (WT, n = 8; H06, n = 10). Recognition index (left panel). *p < 0.05, compared with WT. Investigation time (right panel). *p < 0.05, compared with training. (C) LTM formed by training for 3 min (WT, n = 28; OFF/ON, n = 26; OFF, n = 17). Recognition index (left panel). *p < 0.05, compared with the other groups. Investigation time (right panel). *p < 0.05, compared with training. (D) LTM formed by massed or spaced training (0 min: WT, n = 11; H06, n = 13; 10 min: WT, n = 12; H06, n = 11; 1 h: WT, n = 17; H06, n = 11). Recognition index (left panel). *p < 0.05, compared with the other groups. Investigation time (right panel). *p < 0.05, compared with the first exposure during training. (E) LTM formed by training for 3 min in WT (n = 11) and dnRAR H02 (n = 13) mice. Recognition index (left panel). *p < 0.05. Investigation time (right panel). *p < 0.05, compared with training. Error bars indicate SEM.
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Related In: Results  -  Collection

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Figure 3: Impaired social recognition memory in dnRAR mice and its rescue by stronger training. (A) STM formed by training for 1.5 min (WT, n = 14; H06, n = 15). Recognition index (left panel). *p < 0.05, compared with WT. Investigation time (right panel). *p < 0.05, compared with training. (B) STM formed by training for 3 min (WT, n = 8; H06, n = 10). Recognition index (left panel). *p < 0.05, compared with WT. Investigation time (right panel). *p < 0.05, compared with training. (C) LTM formed by training for 3 min (WT, n = 28; OFF/ON, n = 26; OFF, n = 17). Recognition index (left panel). *p < 0.05, compared with the other groups. Investigation time (right panel). *p < 0.05, compared with training. (D) LTM formed by massed or spaced training (0 min: WT, n = 11; H06, n = 13; 10 min: WT, n = 12; H06, n = 11; 1 h: WT, n = 17; H06, n = 11). Recognition index (left panel). *p < 0.05, compared with the other groups. Investigation time (right panel). *p < 0.05, compared with the first exposure during training. (E) LTM formed by training for 3 min in WT (n = 11) and dnRAR H02 (n = 13) mice. Recognition index (left panel). *p < 0.05. Investigation time (right panel). *p < 0.05, compared with training. Error bars indicate SEM.
Mentions: To investigate the effects of the impaired RAR/RXR signaling pathway on learning and memory, we performed a hippocampus-dependent social recognition memory task. This task measures the difference in the time taken to investigate a juvenile mouse by comparing between the first (training) and second (test) exposures to the mouse [32,33]. We first examined 2 h-short-term memory (STM; Figure 3A). Mice were exposed to a juvenile mouse for 1.5 min during the training and test sessions, which were performed 2 h apart. We measured the social investigation time of WT and OFF/ON-dnRAR H06 mice with the juvenile mouse during the training and test sessions and assessed the recognition index (i.e., the ratio of the social investigation time at the test relative to the training). One-way ANOVA with genotype (dnRAR and WT) revealed a significant effect of genotype (F(1,27) = 12.107, p < 0.05). The post hoc Newman-Keuls test revealed that dnRAR H06 mice showed a significantly worse recognition index than the WT mice (p < 0.05). Consistently, comparison of the social investigation time from the training and test sessions indicated that WT mice, but not OFF/ON-dnRAR H06 mice, displayed a significant decrease in social investigation time during the test compared to the training, indicating that WT mice formed STM, while OFF/ON-dnRAR H06 mice did not. These results indicated that OFF/ON-dnRAR H06 mice have impaired STM.

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Bioscience, Tokyo University of Agriculture, Tokyo, Japan.

ABSTRACT

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 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.

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.

Show MeSH
Related in: MedlinePlus