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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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Related in: MedlinePlus

Basal synaptic transmission and LTP in the hippocampus of dnRAR mice. (A) The input-output relationships of AMPA receptor-mediated EPSP in WT (n = 9) and dnRAR H06 (n = 8) mice. The sample traces in the inset represent the responses evoked with the five different stimulus intensities and the stimulus artifacts were truncated. The data were first sorted by the amplitude range of the fiber volleys, and then the EPSP slopes were averaged within each range. (B) PPF induced by stimulating afferent fibers twice at intervals of 50, 100, 200, and 300 ms in WT (n = 9) and dnRAR H06 (n = 8) mice. (C) PTP induced by high-frequency stimulation (one 100 Hz, 1 s train) in the presence of D-APV (50 μM) in WT (139.2 ± 3.5% of baseline; n = 12) and dnRAR H06 (137.2 ± 4.1% of baseline; n = 10) mice. (D) LTP induced by single conditioning stimulation (one 100 Hz, 1 s train) in WT (n = 30) and dnRAR H06 (n = 16) mice. The initial EPSP slopes were measured, and the values were normalized in each experiment to the averaged slope value measured during the control period (-30 to 0 min). Conditioning stimulation was applied at 0 min. The sample traces in the inset represent the EPSPs (average of 10 consecutive responses) of WT and H06 mice recorded at the times indicated by the letters. The stimulus artifacts were truncated. (E) Summary of LTP induced by single conditioning stimulation in WT and dnRAR H06 mice (21-30 min: WT, 149.5 ± 2.0%; H06, 143.9 ± 3.5%; 51-60 min: WT, 144.1 ± 2.4%; H06, 133.6 ± 3.8%; 111-120 min: WT, 133.3 ± 2.9%; H06, 118.6 ± 3.6%; 171-180 min: WT, 125.0 ± 3.3%; H06, 106.0 ± 4.2% of baseline) (t test, *p < 0.05). (F) LTP induced by strong conditioning stimulation (four 100 Hz, 1 s trains at 5 min intervals) in WT (n = 6) and dnRAR H06 (n = 9) mice. The initial EPSP slopes were measured, and the values were normalized in each experiment to the averaged slope value measured during the control period (-30 to 0 min). Conditioning stimulation was applied at 0 min. The sample traces in the inset represent the EPSPs (average of 10 consecutive responses) of WT and H06 mice recorded at the times indicated by the letters. The stimulus artifacts were truncated. (G) Summary of normalized LTP induced by strong conditioning stimulation in WT and dnRAR H06 mice (21-30 min: WT, 181.4 ± 3.6%; H06, 179.2 ± 3.9%; 51-60 min: WT, 169.9 ± 4.6%; H06, 169.0 ± 3.6%; 111-120 min: WT, 155.3 ± 5.3%; H06, 151.9 ± 5.5%; 171-180 min: WT, 141.7 ± 7.7%; H06, 136.3 ± 6.6% of baseline). (H) STP induced by short conditioning stimulation (one 100 Hz, 100 ms train) in WT (116.2 ± 5.1% of baseline; n = 5) and dnRAR H06 (120.6 ± 8.1% of baseline; n = 5) mice. The initial EPSP slopes were measured, and the values were normalized in each experiment to the averaged slope value measured during the control period (-30 to 0 min). Conditioning stimulation was applied at 0 min. Error bars indicate SEM.
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Figure 2: Basal synaptic transmission and LTP in the hippocampus of dnRAR mice. (A) The input-output relationships of AMPA receptor-mediated EPSP in WT (n = 9) and dnRAR H06 (n = 8) mice. The sample traces in the inset represent the responses evoked with the five different stimulus intensities and the stimulus artifacts were truncated. The data were first sorted by the amplitude range of the fiber volleys, and then the EPSP slopes were averaged within each range. (B) PPF induced by stimulating afferent fibers twice at intervals of 50, 100, 200, and 300 ms in WT (n = 9) and dnRAR H06 (n = 8) mice. (C) PTP induced by high-frequency stimulation (one 100 Hz, 1 s train) in the presence of D-APV (50 μM) in WT (139.2 ± 3.5% of baseline; n = 12) and dnRAR H06 (137.2 ± 4.1% of baseline; n = 10) mice. (D) LTP induced by single conditioning stimulation (one 100 Hz, 1 s train) in WT (n = 30) and dnRAR H06 (n = 16) mice. The initial EPSP slopes were measured, and the values were normalized in each experiment to the averaged slope value measured during the control period (-30 to 0 min). Conditioning stimulation was applied at 0 min. The sample traces in the inset represent the EPSPs (average of 10 consecutive responses) of WT and H06 mice recorded at the times indicated by the letters. The stimulus artifacts were truncated. (E) Summary of LTP induced by single conditioning stimulation in WT and dnRAR H06 mice (21-30 min: WT, 149.5 ± 2.0%; H06, 143.9 ± 3.5%; 51-60 min: WT, 144.1 ± 2.4%; H06, 133.6 ± 3.8%; 111-120 min: WT, 133.3 ± 2.9%; H06, 118.6 ± 3.6%; 171-180 min: WT, 125.0 ± 3.3%; H06, 106.0 ± 4.2% of baseline) (t test, *p < 0.05). (F) LTP induced by strong conditioning stimulation (four 100 Hz, 1 s trains at 5 min intervals) in WT (n = 6) and dnRAR H06 (n = 9) mice. The initial EPSP slopes were measured, and the values were normalized in each experiment to the averaged slope value measured during the control period (-30 to 0 min). Conditioning stimulation was applied at 0 min. The sample traces in the inset represent the EPSPs (average of 10 consecutive responses) of WT and H06 mice recorded at the times indicated by the letters. The stimulus artifacts were truncated. (G) Summary of normalized LTP induced by strong conditioning stimulation in WT and dnRAR H06 mice (21-30 min: WT, 181.4 ± 3.6%; H06, 179.2 ± 3.9%; 51-60 min: WT, 169.9 ± 4.6%; H06, 169.0 ± 3.6%; 111-120 min: WT, 155.3 ± 5.3%; H06, 151.9 ± 5.5%; 171-180 min: WT, 141.7 ± 7.7%; H06, 136.3 ± 6.6% of baseline). (H) STP induced by short conditioning stimulation (one 100 Hz, 100 ms train) in WT (116.2 ± 5.1% of baseline; n = 5) and dnRAR H06 (120.6 ± 8.1% of baseline; n = 5) mice. The initial EPSP slopes were measured, and the values were normalized in each experiment to the averaged slope value measured during the control period (-30 to 0 min). Conditioning stimulation was applied at 0 min. Error bars indicate SEM.

Mentions: We investigated basal synaptic transmission in dnRAR H06 mice. We first analyzed the input-output relationships of AMPA receptor-mediated excitatory postsynaptic potentials (EPSPs) evoked by various stimulus intensities (Figure 2A). We applied a low concentration of CNQX (1 μM) to partially block the AMPA receptors because the fiber volleys were usually much smaller than the EPSPs [29,30]. dnRAR H06 mice showed significantly small AMPA synaptic responses at each presynaptic fiber volley amplitude (PSFV) compared with WT mice (p < 0.05 at each PSFV). These results suggest that AMPA receptor-mediated synaptic responses were decreased in dnRAR H06 mice.


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)

Basal synaptic transmission and LTP in the hippocampus of dnRAR mice. (A) The input-output relationships of AMPA receptor-mediated EPSP in WT (n = 9) and dnRAR H06 (n = 8) mice. The sample traces in the inset represent the responses evoked with the five different stimulus intensities and the stimulus artifacts were truncated. The data were first sorted by the amplitude range of the fiber volleys, and then the EPSP slopes were averaged within each range. (B) PPF induced by stimulating afferent fibers twice at intervals of 50, 100, 200, and 300 ms in WT (n = 9) and dnRAR H06 (n = 8) mice. (C) PTP induced by high-frequency stimulation (one 100 Hz, 1 s train) in the presence of D-APV (50 μM) in WT (139.2 ± 3.5% of baseline; n = 12) and dnRAR H06 (137.2 ± 4.1% of baseline; n = 10) mice. (D) LTP induced by single conditioning stimulation (one 100 Hz, 1 s train) in WT (n = 30) and dnRAR H06 (n = 16) mice. The initial EPSP slopes were measured, and the values were normalized in each experiment to the averaged slope value measured during the control period (-30 to 0 min). Conditioning stimulation was applied at 0 min. The sample traces in the inset represent the EPSPs (average of 10 consecutive responses) of WT and H06 mice recorded at the times indicated by the letters. The stimulus artifacts were truncated. (E) Summary of LTP induced by single conditioning stimulation in WT and dnRAR H06 mice (21-30 min: WT, 149.5 ± 2.0%; H06, 143.9 ± 3.5%; 51-60 min: WT, 144.1 ± 2.4%; H06, 133.6 ± 3.8%; 111-120 min: WT, 133.3 ± 2.9%; H06, 118.6 ± 3.6%; 171-180 min: WT, 125.0 ± 3.3%; H06, 106.0 ± 4.2% of baseline) (t test, *p < 0.05). (F) LTP induced by strong conditioning stimulation (four 100 Hz, 1 s trains at 5 min intervals) in WT (n = 6) and dnRAR H06 (n = 9) mice. The initial EPSP slopes were measured, and the values were normalized in each experiment to the averaged slope value measured during the control period (-30 to 0 min). Conditioning stimulation was applied at 0 min. The sample traces in the inset represent the EPSPs (average of 10 consecutive responses) of WT and H06 mice recorded at the times indicated by the letters. The stimulus artifacts were truncated. (G) Summary of normalized LTP induced by strong conditioning stimulation in WT and dnRAR H06 mice (21-30 min: WT, 181.4 ± 3.6%; H06, 179.2 ± 3.9%; 51-60 min: WT, 169.9 ± 4.6%; H06, 169.0 ± 3.6%; 111-120 min: WT, 155.3 ± 5.3%; H06, 151.9 ± 5.5%; 171-180 min: WT, 141.7 ± 7.7%; H06, 136.3 ± 6.6% of baseline). (H) STP induced by short conditioning stimulation (one 100 Hz, 100 ms train) in WT (116.2 ± 5.1% of baseline; n = 5) and dnRAR H06 (120.6 ± 8.1% of baseline; n = 5) mice. The initial EPSP slopes were measured, and the values were normalized in each experiment to the averaged slope value measured during the control period (-30 to 0 min). Conditioning stimulation was applied at 0 min. Error bars indicate SEM.
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Figure 2: Basal synaptic transmission and LTP in the hippocampus of dnRAR mice. (A) The input-output relationships of AMPA receptor-mediated EPSP in WT (n = 9) and dnRAR H06 (n = 8) mice. The sample traces in the inset represent the responses evoked with the five different stimulus intensities and the stimulus artifacts were truncated. The data were first sorted by the amplitude range of the fiber volleys, and then the EPSP slopes were averaged within each range. (B) PPF induced by stimulating afferent fibers twice at intervals of 50, 100, 200, and 300 ms in WT (n = 9) and dnRAR H06 (n = 8) mice. (C) PTP induced by high-frequency stimulation (one 100 Hz, 1 s train) in the presence of D-APV (50 μM) in WT (139.2 ± 3.5% of baseline; n = 12) and dnRAR H06 (137.2 ± 4.1% of baseline; n = 10) mice. (D) LTP induced by single conditioning stimulation (one 100 Hz, 1 s train) in WT (n = 30) and dnRAR H06 (n = 16) mice. The initial EPSP slopes were measured, and the values were normalized in each experiment to the averaged slope value measured during the control period (-30 to 0 min). Conditioning stimulation was applied at 0 min. The sample traces in the inset represent the EPSPs (average of 10 consecutive responses) of WT and H06 mice recorded at the times indicated by the letters. The stimulus artifacts were truncated. (E) Summary of LTP induced by single conditioning stimulation in WT and dnRAR H06 mice (21-30 min: WT, 149.5 ± 2.0%; H06, 143.9 ± 3.5%; 51-60 min: WT, 144.1 ± 2.4%; H06, 133.6 ± 3.8%; 111-120 min: WT, 133.3 ± 2.9%; H06, 118.6 ± 3.6%; 171-180 min: WT, 125.0 ± 3.3%; H06, 106.0 ± 4.2% of baseline) (t test, *p < 0.05). (F) LTP induced by strong conditioning stimulation (four 100 Hz, 1 s trains at 5 min intervals) in WT (n = 6) and dnRAR H06 (n = 9) mice. The initial EPSP slopes were measured, and the values were normalized in each experiment to the averaged slope value measured during the control period (-30 to 0 min). Conditioning stimulation was applied at 0 min. The sample traces in the inset represent the EPSPs (average of 10 consecutive responses) of WT and H06 mice recorded at the times indicated by the letters. The stimulus artifacts were truncated. (G) Summary of normalized LTP induced by strong conditioning stimulation in WT and dnRAR H06 mice (21-30 min: WT, 181.4 ± 3.6%; H06, 179.2 ± 3.9%; 51-60 min: WT, 169.9 ± 4.6%; H06, 169.0 ± 3.6%; 111-120 min: WT, 155.3 ± 5.3%; H06, 151.9 ± 5.5%; 171-180 min: WT, 141.7 ± 7.7%; H06, 136.3 ± 6.6% of baseline). (H) STP induced by short conditioning stimulation (one 100 Hz, 100 ms train) in WT (116.2 ± 5.1% of baseline; n = 5) and dnRAR H06 (120.6 ± 8.1% of baseline; n = 5) mice. The initial EPSP slopes were measured, and the values were normalized in each experiment to the averaged slope value measured during the control period (-30 to 0 min). Conditioning stimulation was applied at 0 min. Error bars indicate SEM.
Mentions: We investigated basal synaptic transmission in dnRAR H06 mice. We first analyzed the input-output relationships of AMPA receptor-mediated excitatory postsynaptic potentials (EPSPs) evoked by various stimulus intensities (Figure 2A). We applied a low concentration of CNQX (1 μM) to partially block the AMPA receptors because the fiber volleys were usually much smaller than the EPSPs [29,30]. dnRAR H06 mice showed significantly small AMPA synaptic responses at each presynaptic fiber volley amplitude (PSFV) compared with WT mice (p < 0.05 at each PSFV). These results suggest that AMPA receptor-mediated synaptic responses were decreased in dnRAR H06 mice.

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