title: Oral acetate supplementation attenuates N-methyl D-aspartate receptor hypofunction-induced behavioral phenotypes accompanied by restoration of acetyl-histone homeostasis.
abstract: BACKGROUND
  Aberrations in cellular acetate-utilization processes leading to global histone hypoacetylation have been implicated in the etiology of neuropsychiatric disorders like schizophrenia.
  
  
  OBJECTIVE
  Here, we investigated the role of acetate supplementation in the form of glyceryl triacetate (GTA) for the ability to restore the N-methyl D-aspartate (NMDA) receptor-induced histone hypoacetylation and to ameliorate associated behavioral phenotypes in mice.
  
  
  RESULTS
  Taking cues from the studies in SH-SY5Y cells, we monitored acetylation status of specific lysine residues of histones H3 and H4 (H3K9 and H4K8) to determine the impact of oral GTA supplementation in vivo. Mice treated chronically with MK-801 (10 days; 0.15 mg/kg daily) induced hypoacetylation of H3K9 and H4K8 in the hippocampus. Daily oral supplementation of GTA (2.9 g/kg) was able to prevent this MK801-induced hypoacetylation significantly. Though MK-801-stimulated decreases in acetyl-H3K9 and acetyl-H4K8 were found to be associated with ERK1/2 activation, GTA seemed to act independent of this pathway. Simultaneously, GTA administration was able to attenuate the chronic MK-801-induced cognitive behavior phenotypes in elevated plus maze and novel object recognition tests. Not only MK-801, GTA also demonstrated protective effects against behavioral phenotypes generated by another NMDA receptor antagonist, ketamine. Acute (single injection) ketamine-mediated hyperactivity phenotype and chronic (10 days treatment) ketamine-induced phenotype of exaggerated immobility in forced swim test were ameliorated by GTA.
  
  
  CONCLUSIONS
  The signature behavioral phenotypes induced by acute and chronic regimen of NMDA receptor antagonists seemed to be attenuated by GTA. This study thus provides a therapeutic paradigm of using dietary acetate supplement in psychiatric disorders.
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, 226031, U. P, India.|Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110001, India.
authors.forename: Seema
authors.initials: S
authors.lastname: Singh
authors.affiliation: Chronic Disease Biology Group, Institute of Molecular Medicine, 254 Okhla Industrial Estate, Phase-3, New Delhi, 110020, India.
authors.forename: Arnab
authors.initials: A
authors.lastname: Choudhury
authors.affiliation: Chronic Disease Biology Group, Institute of Molecular Medicine, 254 Okhla Industrial Estate, Phase-3, New Delhi, 110020, India.|Department of Toxicology, Jamia Hamdard, New Delhi, 110062, India.
authors.forename: Priya
authors.initials: P
authors.lastname: Gusain
authors.affiliation: Department of Toxicology, Jamia Hamdard, New Delhi, 110062, India.
authors.forename: Suhel
authors.initials: S
authors.lastname: Parvez
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, 226031, U. P, India.
authors.forename: Gautam
authors.initials: G
authors.lastname: Palit
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, 226031, U. P, India.|Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110001, India.
authors.forename: Shubha
authors.initials: S
authors.lastname: Shukla
authors.affiliation: Chronic Disease Biology Group, Institute of Molecular Medicine, 254 Okhla Industrial Estate, Phase-3, New Delhi, 110020, India. drgangulys@gmail.com.
authors.forename: Surajit
authors.initials: S
authors.lastname: Ganguly
mesh_terms: D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D019175:DNA Methylation / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D051379:Mice; D010641:Phenotype; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012559:Schizophrenia / Q000378:metabolism; D013550:Swimming
chemical_list: D000085:Acetates; D018691:Excitatory Amino Acid Antagonists; D006657:Histones; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine; D016291:Dizocilpine Maleate
keywords: Acetylation; Behavior; Epigenetics; Glyceryl triacetate; Hippocampus; Histone; Ketamine; MK-801; NMDA-receptor; Psychiatry
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