title: Ethanol exposure induces neonatal neurodegeneration by enhancing CB1R Exon1 histone H4K8 acetylation and up-regulating CB1R function causing neurobehavioral abnormalities in adult mice.
abstract: BACKGROUND
  Ethanol exposure to rodents during postnatal day 7 (P7), which is comparable to the third trimester of human pregnancy, induces long-term potentiation and memory deficits. However, the molecular mechanisms underlying these deficits are still poorly understood.
  
  
  METHODS
  In the present study, we explored the potential role of epigenetic changes at cannabinoid type 1 (CB1R) exon1 and additional CB1R functions, which could promote memory deficits in animal models of fetal alcohol spectrum disorder.
  
  
  RESULTS
  We found that ethanol treatment of P7 mice enhances acetylation of H4 on lysine 8 (H4K8ace) at CB1R exon1, CB1R binding as well as the CB1R agonist-stimulated GTPγS binding in the hippocampus and neocortex, two brain regions that are vulnerable to ethanol at P7 and are important for memory formation and storage, respectively. We also found that ethanol inhibits cyclic adenosine monophosphate response element-binding protein (CREB) phosphorylation and activity-regulated cytoskeleton-associated protein (Arc) expression in neonatal and adult mice. The blockade or genetic deletion of CB1Rs prior to ethanol treatment at P7 rescued CREB phosphorylation and Arc expression. CB1R knockout mice exhibited neither ethanol-induced neurodegeneration nor inhibition of CREB phosphorylation or Arc expression. However, both neonatal and adult mice did exhibit enhanced CREB phosphorylation and Arc protein expression. P7 ethanol-treated adult mice exhibited impaired spatial and social recognition memory, which were prevented by the pharmacological blockade or deletion of CB1Rs at P7.
  
  
  CONCLUSIONS
  Together, these findings suggest that P7 ethanol treatment induces CB1R expression through epigenetic modification of the CB1R gene, and that the enhanced CB1R function induces pCREB, Arc, spatial, and social memory deficits in adult mice.
authors.affiliation: Division of Analytical Psychopharmacology, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY (Drs Subbanna, Nagre, and Basavarajappa); Vascular Biology Center, Georgia Regents University, Augusta, GA (Dr Umapathy); Department of Pediatrics, Georgia Regents University, Augusta, GA (Dr Pace); New York State Psychiatric Institute, New York, NY (Dr Basavarajappa); Department of Psychiatry, College of Physicians & Surgeons, Columbia University, New York, NY (Dr Basavarajappa).
authors.forename: Shivakumar
authors.initials: S
authors.lastname: Subbanna
authors.affiliation: Division of Analytical Psychopharmacology, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY (Drs Subbanna, Nagre, and Basavarajappa); Vascular Biology Center, Georgia Regents University, Augusta, GA (Dr Umapathy); Department of Pediatrics, Georgia Regents University, Augusta, GA (Dr Pace); New York State Psychiatric Institute, New York, NY (Dr Basavarajappa); Department of Psychiatry, College of Physicians & Surgeons, Columbia University, New York, NY (Dr Basavarajappa).
authors.forename: Nagaraja N
authors.initials: NN
authors.lastname: Nagre
authors.affiliation: Division of Analytical Psychopharmacology, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY (Drs Subbanna, Nagre, and Basavarajappa); Vascular Biology Center, Georgia Regents University, Augusta, GA (Dr Umapathy); Department of Pediatrics, Georgia Regents University, Augusta, GA (Dr Pace); New York State Psychiatric Institute, New York, NY (Dr Basavarajappa); Department of Psychiatry, College of Physicians & Surgeons, Columbia University, New York, NY (Dr Basavarajappa).
authors.forename: Nagavedi S
authors.initials: NS
authors.lastname: Umapathy
authors.affiliation: Division of Analytical Psychopharmacology, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY (Drs Subbanna, Nagre, and Basavarajappa); Vascular Biology Center, Georgia Regents University, Augusta, GA (Dr Umapathy); Department of Pediatrics, Georgia Regents University, Augusta, GA (Dr Pace); New York State Psychiatric Institute, New York, NY (Dr Basavarajappa); Department of Psychiatry, College of Physicians & Surgeons, Columbia University, New York, NY (Dr Basavarajappa).
authors.forename: Betty S
authors.initials: BS
authors.lastname: Pace
authors.affiliation: Division of Analytical Psychopharmacology, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY (Drs Subbanna, Nagre, and Basavarajappa); Vascular Biology Center, Georgia Regents University, Augusta, GA (Dr Umapathy); Department of Pediatrics, Georgia Regents University, Augusta, GA (Dr Pace); New York State Psychiatric Institute, New York, NY (Dr Basavarajappa); Department of Psychiatry, College of Physicians & Surgeons, Columbia University, New York, NY (Dr Basavarajappa). Basavaraj@nki.rfmh.org.
authors.forename: Balapal S
authors.initials: BS
authors.lastname: Basavarajappa
mesh_terms: D000386:AIDS-Related Complex / Q000378:metabolism; D000107:Acetylation / Q000187:drug effects; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism / Q000523:psychology; D050882:CREB-Binding Protein / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000633:toxicity; D044127:Epigenesis, Genetic / Q000187:drug effects; D000431:Ethanol / Q000633:toxicity*; D005091:Exons / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006657:Histones / Q000235:genetics; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019579:Neocortex / Q000187:drug effects / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000523:psychology; D010766:Phosphorylation / Q000187:drug effects; D043884:Receptor, Cannabinoid, CB1 / Q000172:deficiency / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D012919:Social Behavior; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D002492:Central Nervous System Depressants; D006657:Histones; D043884:Receptor, Cannabinoid, CB1; D000431:Ethanol; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse
keywords: FASD; cannabinoid receptor system; epigenetics; memory loss; synaptic signaling