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Reducing HDAC6 ameliorates cognitive deficits in a mouse model for Alzheimer's disease.

Govindarajan N, Rao P, Burkhardt S, Sananbenesi F, Schlüter OM, Bradke F, Lu J, Fischer A - EMBO Mol Med (2012)

Bottom Line: However, the role of specific HDACs in cognition and neurodegeneration remains poorly understood.Our data suggest that this therapeutic effect is, at least in part, linked to the observation that loss of HDAC6 renders neurons resistant to amyloid-β-mediated impairment of mitochondrial trafficking.Thus, our study suggests that targeting HDAC6 could be a suitable strategy to ameliorate cognitive decline observed in AD.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August-University Goettingen, Goettingen, Germany.

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Related in: MedlinePlus

Behavioral analysis of Hdac6−/− miceRepresentative images showing exploratory behaviour in the open field test.Total distance covered during a 5 min open field exposure by Hdac6−/− and wild type mice (n = 10).The time spent in the center versus periphery of the open field in Hdac6−/− and wild type mice (n = 10).Motor function was analysed in the Rotarod test. Time spent on the rotating rod in Hdac6−/− and wild type mice (n = 10).The total activity and the response to the electric foot shock in the contextual fear conditioning paradigm in Hdac6−/− and wild type mice (n = 10).Contextual freezing behaviour assessed 24 h after the training in Hdac6−/− and wild type mice (n = 10).Escape latency during the training phase of the Morris water maze in Hdac6−/− and wild type mice (n = 15).Time spent in the target quadrant during the probe test in Hdac6−/− and wild type mice (n = 15). Values are mean ± SEM *p = 0.0384, ***p = 0.0001, analysed by Student's t-test. QT, Target quadrant.
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fig02: Behavioral analysis of Hdac6−/− miceRepresentative images showing exploratory behaviour in the open field test.Total distance covered during a 5 min open field exposure by Hdac6−/− and wild type mice (n = 10).The time spent in the center versus periphery of the open field in Hdac6−/− and wild type mice (n = 10).Motor function was analysed in the Rotarod test. Time spent on the rotating rod in Hdac6−/− and wild type mice (n = 10).The total activity and the response to the electric foot shock in the contextual fear conditioning paradigm in Hdac6−/− and wild type mice (n = 10).Contextual freezing behaviour assessed 24 h after the training in Hdac6−/− and wild type mice (n = 10).Escape latency during the training phase of the Morris water maze in Hdac6−/− and wild type mice (n = 15).Time spent in the target quadrant during the probe test in Hdac6−/− and wild type mice (n = 15). Values are mean ± SEM *p = 0.0384, ***p = 0.0001, analysed by Student's t-test. QT, Target quadrant.

Mentions: Next, we subjected Hdac6−/− and wild type mice to behavioural testing. Exploratory behaviour was unaltered in Hdac6−/− mice when compared to wild type littermates. Both groups showed indistinguishable activity when exposed to a novel context (Fig 2A and B). Moreover, the time spent in the centre versus periphery of the open field was similar between groups indicating no changes in basal anxiety (Fig 2C). Motor coordination that was measured using the accelerating rotarod test was similar in Hdac6−/− mice and wild type littermates (Fig 2D). When exposed to contextual fear conditioning, a robust test to assess associative memory function, Hdac6−/− mice showed normal activity during the training and the response to the electric foot shock was indistinguishable from the control group (Fig 2E). Long-term associative memory, measured via the assessment of freezing behaviour upon re-exposure to the conditioning context 24 h after the training was not different between the two groups (Fig 2F). Finally, we measured spatial learning using the Morris Water Maze paradigm, a well-established and sensitive test to measure hippocampus-dependent spatial memory function. While the escape latency throughout 6 days of training was similar between groups (Fig 2G), during the subsequent memory test Hdac6−/− mice showed a significantly increased preference for the target region when compared to the wild type control group (Fig 2H). Two-way ANOVA revealed no effect of gender on any of the above-described behaviour tests. In conclusion, these data suggest that loss of HDAC6 has no detrimental effect on brain morphology, motor coordination, or hippocampus-dependent cognitive function.


Reducing HDAC6 ameliorates cognitive deficits in a mouse model for Alzheimer's disease.

Govindarajan N, Rao P, Burkhardt S, Sananbenesi F, Schlüter OM, Bradke F, Lu J, Fischer A - EMBO Mol Med (2012)

Behavioral analysis of Hdac6−/− miceRepresentative images showing exploratory behaviour in the open field test.Total distance covered during a 5 min open field exposure by Hdac6−/− and wild type mice (n = 10).The time spent in the center versus periphery of the open field in Hdac6−/− and wild type mice (n = 10).Motor function was analysed in the Rotarod test. Time spent on the rotating rod in Hdac6−/− and wild type mice (n = 10).The total activity and the response to the electric foot shock in the contextual fear conditioning paradigm in Hdac6−/− and wild type mice (n = 10).Contextual freezing behaviour assessed 24 h after the training in Hdac6−/− and wild type mice (n = 10).Escape latency during the training phase of the Morris water maze in Hdac6−/− and wild type mice (n = 15).Time spent in the target quadrant during the probe test in Hdac6−/− and wild type mice (n = 15). Values are mean ± SEM *p = 0.0384, ***p = 0.0001, analysed by Student's t-test. QT, Target quadrant.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
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getmorefigures.php?uid=PMC3569653&req=5

fig02: Behavioral analysis of Hdac6−/− miceRepresentative images showing exploratory behaviour in the open field test.Total distance covered during a 5 min open field exposure by Hdac6−/− and wild type mice (n = 10).The time spent in the center versus periphery of the open field in Hdac6−/− and wild type mice (n = 10).Motor function was analysed in the Rotarod test. Time spent on the rotating rod in Hdac6−/− and wild type mice (n = 10).The total activity and the response to the electric foot shock in the contextual fear conditioning paradigm in Hdac6−/− and wild type mice (n = 10).Contextual freezing behaviour assessed 24 h after the training in Hdac6−/− and wild type mice (n = 10).Escape latency during the training phase of the Morris water maze in Hdac6−/− and wild type mice (n = 15).Time spent in the target quadrant during the probe test in Hdac6−/− and wild type mice (n = 15). Values are mean ± SEM *p = 0.0384, ***p = 0.0001, analysed by Student's t-test. QT, Target quadrant.
Mentions: Next, we subjected Hdac6−/− and wild type mice to behavioural testing. Exploratory behaviour was unaltered in Hdac6−/− mice when compared to wild type littermates. Both groups showed indistinguishable activity when exposed to a novel context (Fig 2A and B). Moreover, the time spent in the centre versus periphery of the open field was similar between groups indicating no changes in basal anxiety (Fig 2C). Motor coordination that was measured using the accelerating rotarod test was similar in Hdac6−/− mice and wild type littermates (Fig 2D). When exposed to contextual fear conditioning, a robust test to assess associative memory function, Hdac6−/− mice showed normal activity during the training and the response to the electric foot shock was indistinguishable from the control group (Fig 2E). Long-term associative memory, measured via the assessment of freezing behaviour upon re-exposure to the conditioning context 24 h after the training was not different between the two groups (Fig 2F). Finally, we measured spatial learning using the Morris Water Maze paradigm, a well-established and sensitive test to measure hippocampus-dependent spatial memory function. While the escape latency throughout 6 days of training was similar between groups (Fig 2G), during the subsequent memory test Hdac6−/− mice showed a significantly increased preference for the target region when compared to the wild type control group (Fig 2H). Two-way ANOVA revealed no effect of gender on any of the above-described behaviour tests. In conclusion, these data suggest that loss of HDAC6 has no detrimental effect on brain morphology, motor coordination, or hippocampus-dependent cognitive function.

Bottom Line: However, the role of specific HDACs in cognition and neurodegeneration remains poorly understood.Our data suggest that this therapeutic effect is, at least in part, linked to the observation that loss of HDAC6 renders neurons resistant to amyloid-β-mediated impairment of mitochondrial trafficking.Thus, our study suggests that targeting HDAC6 could be a suitable strategy to ameliorate cognitive decline observed in AD.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August-University Goettingen, Goettingen, Germany.

Show MeSH
Related in: MedlinePlus