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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 by the pharmacological inhibition of hippocampal RARα. Recognition index (left panel). Effects of micro-infused Ro41-5253 (Ro41; 242 pg/side) into the dorsal hippocampus at 1, 4, or 24 h before training and the effects of micro-infused low-dose Ro41 (24 pg/side) on 24 h LT-social recognition memory (VEH, n = 38; 1 h, n = 12; 4 h-low, n = 11; 4 h, n = 13; 24 h, n = 12). *p < 0.05, compared with the VEH group. Investigation time (right panel). *p < 0.05, compared with training. The lower panel indicates cannula tip placement in mice infused with VEH or Ro41.
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Figure 5: Impaired social recognition memory by the pharmacological inhibition of hippocampal RARα. Recognition index (left panel). Effects of micro-infused Ro41-5253 (Ro41; 242 pg/side) into the dorsal hippocampus at 1, 4, or 24 h before training and the effects of micro-infused low-dose Ro41 (24 pg/side) on 24 h LT-social recognition memory (VEH, n = 38; 1 h, n = 12; 4 h-low, n = 11; 4 h, n = 13; 24 h, n = 12). *p < 0.05, compared with the VEH group. Investigation time (right panel). *p < 0.05, compared with training. The lower panel indicates cannula tip placement in mice infused with VEH or Ro41.

Mentions: Our observations that dnRAR expression in the forebrain led to impairments of hippocampal synaptic transmission and plasticity and the formation of two different types of hippocampus-dependent memories suggest that the RAR/RXR signaling pathway plays a crucial role in hippocampus-dependent memory. To further understand the roles of RARα in the hippocampus, we examined the effects of the pharmacological blockade of RARα in the hippocampus on LT-social recognition memory using a micro-infusion of Ro41-5253 (Ro41), a selective antagonist of RARα, into the dorsal hippocampus. WT mice were trained and tested 24 h later with exposure to a juvenile mouse for 3 min. The mice received a micro-infusion of vehicle (VEH) or Ro41 (242 pg/side) into the dorsal hippocampus at 1, 4, or 24 h, respectively, before training (Figure 5A). One-way ANOVA revealed a significant effect of group (F(3,53) = 5.460, p < 0.05). The mice infused with Ro41 at 4 h before training displayed a significantly worse recognition index than the other groups (p < 0.05), which displayed comparable recognition indices (p > 0.05). Consistently, the mice infused with Ro41 at 4 h before training failed to decrease their social investigation time during the test compared with training, while the other groups displayed significant decreases in their social investigation time. These observations indicated that the microinfusion of Ro41 into the hippocampus impairs social recognition memory within a time window that impairs memory performance. We also examined the dose-dependent effects of Ro41 on the impairment of LT-social recognition memory. WT mice received a low-dose microinfusion of Ro41 (24 pg/side) into the dorsal hippocampus at 4 h before training. One-way ANOVA with drug (VEH and the low and high dose groups) revealed a significant effect of group (F(2,41) = 8.046, p < 0.05). The mice that received a high dose of Ro41 displayed a significantly worse recognition index than the VEH group (p < 0.05), whereas the mice that received a low dose of Ro41 displayed a comparable recognition index with the mice infused with VEH or a high dose of Ro41 (p > 0.05). Consistently, the mice that were infused with a low dose of Ro41 displayed a significant decrease in social investigation time during the test compared with training, while the mice infused with a high dose of Ro41 did not. These observations indicated that the micro-infusion of Ro41 into the hippocampus impairs social recognition memory in a dose-dependent manner. Collectively, our observations indicated that the blockade of RARα in the hippocampus impairs social recognition memory, suggesting that the RAR/RXR signaling pathway in the hippocampus is crucial for social recognition memory.


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 by the pharmacological inhibition of hippocampal RARα. Recognition index (left panel). Effects of micro-infused Ro41-5253 (Ro41; 242 pg/side) into the dorsal hippocampus at 1, 4, or 24 h before training and the effects of micro-infused low-dose Ro41 (24 pg/side) on 24 h LT-social recognition memory (VEH, n = 38; 1 h, n = 12; 4 h-low, n = 11; 4 h, n = 13; 24 h, n = 12). *p < 0.05, compared with the VEH group. Investigation time (right panel). *p < 0.05, compared with training. The lower panel indicates cannula tip placement in mice infused with VEH or Ro41.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 5: Impaired social recognition memory by the pharmacological inhibition of hippocampal RARα. Recognition index (left panel). Effects of micro-infused Ro41-5253 (Ro41; 242 pg/side) into the dorsal hippocampus at 1, 4, or 24 h before training and the effects of micro-infused low-dose Ro41 (24 pg/side) on 24 h LT-social recognition memory (VEH, n = 38; 1 h, n = 12; 4 h-low, n = 11; 4 h, n = 13; 24 h, n = 12). *p < 0.05, compared with the VEH group. Investigation time (right panel). *p < 0.05, compared with training. The lower panel indicates cannula tip placement in mice infused with VEH or Ro41.
Mentions: Our observations that dnRAR expression in the forebrain led to impairments of hippocampal synaptic transmission and plasticity and the formation of two different types of hippocampus-dependent memories suggest that the RAR/RXR signaling pathway plays a crucial role in hippocampus-dependent memory. To further understand the roles of RARα in the hippocampus, we examined the effects of the pharmacological blockade of RARα in the hippocampus on LT-social recognition memory using a micro-infusion of Ro41-5253 (Ro41), a selective antagonist of RARα, into the dorsal hippocampus. WT mice were trained and tested 24 h later with exposure to a juvenile mouse for 3 min. The mice received a micro-infusion of vehicle (VEH) or Ro41 (242 pg/side) into the dorsal hippocampus at 1, 4, or 24 h, respectively, before training (Figure 5A). One-way ANOVA revealed a significant effect of group (F(3,53) = 5.460, p < 0.05). The mice infused with Ro41 at 4 h before training displayed a significantly worse recognition index than the other groups (p < 0.05), which displayed comparable recognition indices (p > 0.05). Consistently, the mice infused with Ro41 at 4 h before training failed to decrease their social investigation time during the test compared with training, while the other groups displayed significant decreases in their social investigation time. These observations indicated that the microinfusion of Ro41 into the hippocampus impairs social recognition memory within a time window that impairs memory performance. We also examined the dose-dependent effects of Ro41 on the impairment of LT-social recognition memory. WT mice received a low-dose microinfusion of Ro41 (24 pg/side) into the dorsal hippocampus at 4 h before training. One-way ANOVA with drug (VEH and the low and high dose groups) revealed a significant effect of group (F(2,41) = 8.046, p < 0.05). The mice that received a high dose of Ro41 displayed a significantly worse recognition index than the VEH group (p < 0.05), whereas the mice that received a low dose of Ro41 displayed a comparable recognition index with the mice infused with VEH or a high dose of Ro41 (p > 0.05). Consistently, the mice that were infused with a low dose of Ro41 displayed a significant decrease in social investigation time during the test compared with training, while the mice infused with a high dose of Ro41 did not. These observations indicated that the micro-infusion of Ro41 into the hippocampus impairs social recognition memory in a dose-dependent manner. Collectively, our observations indicated that the blockade of RARα in the hippocampus impairs social recognition memory, suggesting that the RAR/RXR signaling pathway in the hippocampus is crucial for social recognition memory.

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