title: Histone Deacetylase 2 Inhibition Attenuates Downregulation of Hippocampal Plasticity Gene Expression during Aging.
abstract: The brain undergoes several anatomical, biochemical, and molecular changes during aging, which subsequently result in downregulation of synaptic plasticity genes and decline of memory. However, the regulation of these genes during aging is not clearly understood. Previously, we reported that the expression of histone deacetylase (HDAC)2 was upregulated in the hippocampus of old mice and negatively correlated with the decline in recognition memory. As HDAC2 regulates key synaptic plasticity neuronal immediate early genes (IEGs), we have examined their expression and epigenetic regulation. We noted that the expression of neuronal IEGs decreased both at mRNA and protein level in the hippocampus of old mice. To explore the underlying regulation, we analyzed the binding of HDAC2 and level of histone acetylation at the promoter of neuronal IEGs. While the binding of HDAC2 was higher, H3K9 and H3K14 acetylation level was lower at the promoter of these genes in old as compared to young and adult mice. Further, we inhibited HDAC2 non-specifically by sodium butyrate and specifically by antisense oligonucleotide to recover epigenetic modification, expression of neuronal IEGs, and memory in old mice. Inhibition of HDAC2 increased histone H3K9 and H3K14 acetylation level at the promoter of neuronal IEGs, their expression, and recognition memory in old mice as compared to control. Thus, inhibition of HDAC2 can be used as a therapeutic target to recover decline in memory due to aging and associated neurological disorders.
authors.affiliation: Biochemistry and Molecular Biology Laboratory, Centre of Advanced Study, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, 221 005, India.
authors.forename: Padmanabh
authors.initials: P
authors.lastname: Singh
authors.affiliation: Biochemistry and Molecular Biology Laboratory, Centre of Advanced Study, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, 221 005, India. mkt_bhu@yahoo.com.
authors.forename: M K
authors.initials: MK
authors.lastname: Thakur
mesh_terms: D000375:Aging / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000502:physiology*; D015870:Gene Expression; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D056572:Histone Deacetylase Inhibitors / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*
chemical_list: D056572:Histone Deacetylase Inhibitors; C533424:Hdac2 protein, mouse; D056464:Histone Deacetylase 2
keywords: HDAC inhibitor; HDAC2; Histone acetylation; Memory; Neuronal IEG