Reassessing the effects of histone deacetylase inhibitors on hippocampal memory and cognitive aging.
Hippocampus
; 24(8): 1006-16, 2014 Aug.
Article
em En
| MEDLINE
| ID: mdl-24753063
ABSTRACT
Converging results link histone acetylation dynamics to hippocampus-dependent memory, including evidence that histone deacetylase inhibitor (HDACi) administration enhances long-term memory. Previously, we demonstrated that aging disrupts the coordinated epigenetic response to recent experience observed in the young adult hippocampus. Here, we extended that work to test the cognitive effects of a novel, brain-penetrant HDACi (EVX001688; EVX) that we confirmed yields robust, relatively long lasting dose-dependent increases in histone acetylation in the hippocampus. In young rats, acute systemic EVX administration, scheduled to yield elevated histone acetylation levels during training in a contextual fear conditioning (CFC) task, had no effect on memory retention at 24 h at any dose examined (10, 30, or 60 mg/kg). Pretraining injection of another HDACi, sodium butyrate, also failed to affect fear memory, and CFC training itself had no influence on hippocampal histone acetylation at 1 hour in mice or two strains of rats. EVX administration before water maze training in young rats yielded a modest effect such that the middle dose produced marginally better 24-h retention than either the low or high dose, but only a small numerical benefit relative to vehicle. Guided by those findings, a final experiment tested the influence of pretraining EVX treatment on age-related spatial memory impairment. The results, revealing no effect on performance, are consistent with the idea that effective procognitive HDACi treatments in aging may require intervention aimed at restoring coordinated epigenetic regulation rather than bulk increases in hippocampal histone acetylation.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Envelhecimento
/
Cognição
/
Inibidores de Histona Desacetilases
/
Hipocampo
/
Memória
Limite:
Animals
Idioma:
En
Revista:
Hippocampus
Ano de publicação:
2014
Tipo de documento:
Article