| Converging evidence links chromatin regulation to memory-related synaptic plasticity. Here, we evaluated chromatin modification dynamics in normal cognitive aging and the ameliorative potential of epigenome-targeted pharmacotherapy. Our results point to a contribution of bidirectional, modification-specific regulation of histone acetylation in neurocognitive aging. Overall, age-related memory impairment was associated with disrupted coordination across a constellation of epigenetic modifications, rather than deficits in a single mechanism. Building on our data implicating a role for histone acetylation in age-related memory impairment, we evaluated the pharmacological and behavioral effects of histone deacetylase (HDAC) inhibition in young and cognitively impaired aged rats using a novel brain penetrant HDAC inhibitor. Modest, dose-dependent improvements in water maze performance were observed in both young and aged rats with systemic, pre-training drug administration. Our pharmacologic data suggest that optimizing memory may require a previously unappreciated degree of histone acetylation regulation. Taken together, our results reveal a highly coordinated, specific role for epigenetic mechanisms in memory functioning and normal cognitive aging. |
