title: Pre-administration of G9a/GLP inhibitor during synaptogenesis prevents postnatal ethanol-induced LTP deficits and neurobehavioral abnormalities in adult mice.
abstract: It has been widely accepted that deficits in neuronal plasticity underlie the cognitive abnormalities observed in fetal alcohol spectrum disorder (FASD). Exposure of rodents to acute ethanol on postnatal day 7 (P7), which is equivalent to the third trimester of fetal development in human, induces long-term potentiation (LTP) and memory deficits in adult animals. However, the molecular mechanisms underlying these deficits are not well understood. Recently, we found that histone H3 dimethylation (H3K9me2), which is mediated by G9a (lysine dimethyltransferase), is responsible for the neurodegeneration caused by ethanol exposure in P7 mice. In addition, pharmacological inhibition of G9a prior to ethanol treatment at P7 normalized H3K9me2 proteins to basal levels and prevented neurodegeneration in neonatal mice. Here, we tested the hypothesis that pre-administration of G9a/GLP inhibitor (Bix-01294, Bix) in conditions in which ethanol induces neurodegeneration would be neuroprotective against P7 ethanol-induced deficits in LTP, memory and social recognition behavior in adult mice. Ethanol treatment at P7 induces deficits in LTP, memory and social recognition in adult mice and these deficits were prevented by Bix pretreatment at P7. Together, these findings provide physiological and behavioral evidence that the long-term harmful consequences on brain function after ethanol exposure with a third trimester equivalent have an epigenetic origin.
authors.affiliation: Division of Analytical Psychopharmacology, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA.
authors.forename: Shivakumar
authors.initials: S
authors.lastname: Subbanna
authors.affiliation: Division of Analytical Psychopharmacology, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA; New York State Psychiatric Institute, New York, NY 10032, USA; Department of Psychiatry, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA. Electronic address: Basavaraj@nki.rfmh.org.
authors.forename: Balapal S
authors.initials: BS
authors.lastname: Basavarajappa
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001381:Azepines / Q000008:administration & dosage*; D002492:Central Nervous System Depressants / Q000633:toxicity*; D004334:Drug Administration Schedule; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D000431:Ethanol / Q000633:toxicity*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced* / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D055495:Neurogenesis / Q000187:drug effects; D011799:Quinazolines / Q000008:administration & dosage*; D021641:Recognition, Psychology / Q000187:drug effects; D012919:Social Behavior
chemical_list: D001381:Azepines; C518299:BIX 01294; D002492:Central Nervous System Depressants; D004791:Enzyme Inhibitors; D011799:Quinazolines; D000431:Ethanol; D011495:Histone-Lysine N-Methyltransferase
keywords: Bix; Epigenetics; Ethanol; FASD; H3K9; Histones; Memory loss; Methyltransferase; Postnatal development; Synaptic plasticity