Age-Related Memory Impairment Is Associated with Disrupted Multivariate Epigenetic Coordination in the Hippocampus

Abstract

Mounting evidence linking epigenetic regulation to memory-related synaptic plasticity raises the possibility that altered chromatin modification dynamics might contribute to age-dependent cognitive decline. Here we show that the coordinated orchestration of both baseline and experience-dependent epigenetic regulation seen in the young adult hippocampus is lost in association with cognitive aging. Using a well-characterized rat model that reliably distinguishes aged individuals with significant memory impairment from others with normal memory, no single epigenetic mark or experience-dependent modification in the hippocampus uniquely predicted differences in the cognitive outcome of aging. The results instead point to a multivariate pattern in which modification-specific, bidirectional chromatin regulation is dependent on recent behavioral experience, chronological age, cognitive status, and hippocampal region. Whereas many epigenetic signatures were coupled with memory capacity among young adults and aged rats with preserved cognitive function, such associations were absent among aged rats with deficits in hippocampal memory. By comparison with the emphasis in current preclinical translational research on promoting chromatin modifications permissive for gene expression, our findings suggest that optimally successful hippocampal aging may hinge instead on enabling coordinated control across the epigenetic landscape.

Reassessing the effects of histone deacetylase inhibitors on hippocampal memory and cognitive aging

“…Age-related deficits revealed by this model are associated with disrupted epigenetic regulation in the hippocampus (Castellano et al, 2012), and are sensitive to rescue by pharmacological intervention targeting a variety of mechanisms (Koh et al, 2013;. A pilot study in a small number of aged rats revealed that, consistent with results for exploratory activity in young subjects (Fig.…”

“…Redundant Place-Cue Training-Approximately two weeks after standard background training, rats were tested on a redundant place-cue task (RPC) in a new spatial environment (Castellano et al, 2012). Training consisted of 15 trials with an escape platform held in a constant location (15 sec intertrial interval), and a probe trial 24 hr after the first training trial.…”

Epigenetic regulation of memory formation and maintenance

“…In fact, exposure to a novel environment produced increased levels of ERK1/2 dependent H3 phosphorylation and acetylation that was abolished by environmental habituation (Sarantis et al 2012). Similarly, context exposure alone produced increased H3K9me2 in the CA1 (Gupta-Agarwal et al 2012) and exposure to a visible-platform control condition produced similar changes in H3 acetylation to those seen after MWM training (Castellano et al 2012). With respect to DNA methylation, the specificity of the changes observed in response to the context and shock pairing is dependent on the gene of interest, with some genes, including egr1/zif268 and bdnf exon 1, exhibiting similar modifications when shock and context are presented individually as when they are presented in combination (Lubin et al 2008;Miller et al 2010).…”

“…Using peptide array technology, Castellano et al (2012) showed that several of their purchased antibodies recognized various histone modifications in addition to the ones supposedly targeted by their antibodies. This lack of antibody specificity has important implications for both past and future studies that examine how combinatorial patterns of histone modifications work together to regulate gene expression.…”

Epigenetic regulation of memory: implications in human cognitive disorders

“…Furthermore, mice with deletion of the Hdac2 gene showed enhanced LTM, in response to fear conditioning, while overexpression of Hdac2 in the mouse brain decreased LTM (47). Several other studies have also indicated that limiting HDAC2 levels is critical for optimal cognitive ability during aging (54)(55)(56). HDAC2 was found to be elevated in Alzheimer's disease brains and in mouse models for neurodegenerative disease, which have defects in spatial memory and fear conditioning (54).…”