Experience Modulates the Effects of Histone Deacetylase Inhibitors on Gene and Protein Expression in the Hippocampus: Impaired Plasticity in Aging.
The therapeutic potential of histone deacetylase inhibitor (HDACi) treatment has attracted considerable attention in the emerging area of cognitive neuroepigenetics. The possibility that ongoing cognitive experience importantly regulates the cell biological effects of HDACi administration, however, has not been systematically examined. In an initial experiment addressing this issue, we tested whether water maze training influences the gene expression response to acute systemic HDACi administration in the young adult rat hippocampus. Training powerfully modulated the response to HDACi treatment, increasing the total number of genes regulated to nearly 3000, including many not typically linked to neural plasticity, compared with <300 following HDACi administration alone. Although water maze training itself also regulated nearly 1800 genes, the specific mRNAs, gene networks, and biological pathways involved were largely distinct when the same experience was provided together with HDACi administration. Next, we tested whether the synaptic protein response to HDACi treatment is similarly dependent on recent cognitive experience, and whether this plasticity is altered in aged rats with memory impairment. Whereas synaptic protein labeling in the young hippocampus was selectively increased when HDACi administration was provided in conjunction with water maze training, combined treatment had no effect on synaptic proteins in the aged hippocampus. Our findings indicate that ongoing experience potently regulates the molecular consequences of HDACi treatment and that the interaction of recent cognitive experience with histone acetylation dynamics is disrupted in the aged hippocampus.


CONCLUSIONS
The possibility that interventions targeting epigenetic regulation could be effective in treating a range of neurodegenerative disorders has attracted considerable interest. Here we demonstrate in the rat hippocampus that ongoing experience powerfully modifies the molecular response to one such intervention, histone deacetylase inhibitor (HDACi) administration. A single learning episode dramatically shifts the gene expression profile induced by acute HDACi treatment, yielding a qualitatively distinct hippocampal transcriptome compared with the influence of behavioral training alone. The downstream synaptic protein response to HDACi administration is similarly experience-dependent, and we report that this plasticity is disrupted in the aged hippocampus. The findings highlight that accommodating the modulatory influence of ongoing experience represents a challenge for therapeutic development in the area of cognitive neuroepigenetics.
Neurocognitive Aging Section, National Institute on Aging, Baltimore, Maryland 21224, Graduate Program in Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
Angila S
AS
Sewal
FORUM Pharmaceuticals, Waltham, Massachusetts 02451, and.
Holger
H
Patzke
Neurocognitive Aging Section, National Institute on Aging, Baltimore, Maryland 21224.
Evelyn J
EJ
Perez
Neurocognitive Aging Section, National Institute on Aging, Baltimore, Maryland 21224.
Pul
P
Park
Gene Expression and Genomics Unit, National Institute on Aging, Baltimore, Maryland 21224.
Elin
http://orcid.org/0000-0002-9869-9475
E
Lehrmann
Gene Expression and Genomics Unit, National Institute on Aging, Baltimore, Maryland 21224.
Yongqing
Y
Zhang
Gene Expression and Genomics Unit, National Institute on Aging, Baltimore, Maryland 21224.
Kevin G
KG
Becker
Neurocognitive Aging Section, National Institute on Aging, Baltimore, Maryland 21224.
Bonnie R
BR
Fletcher
Neurocognitive Aging Section, National Institute on Aging, Baltimore, Maryland 21224.
Jeffrey M
JM
Long
Neurocognitive Aging Section, National Institute on Aging, Baltimore, Maryland 21224, rappp@mail.nih.gov.
Peter R
PR
Rapp
D000375:Aging / Q000502:physiology*; D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D008297:Male; D057567:Memory, Long-Term / Q000187:drug effects / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344
D056572:Histone Deacetylase Inhibitors; D009419:Nerve Tissue Proteins
cognitive aging; epigenetics; histone acetylation; microarray; synaptic protein