PMID- 29691979 OWN - NLM STAT- MEDLINE DCOM- 20190501 LR - 20200306 IS - 1601-183X (Electronic) IS - 1601-1848 (Print) IS - 1601-183X (Linking) VI - 18 IP - 3 DP - 2019 Mar TI - The brain-derived neurotrophic factor VAL68MET polymorphism modulates how developmental ethanol exposure impacts the hippocampus. PG - e12484 LID - 10.1111/gbb.12484 [doi] AB - Prenatal exposure to alcohol causes a wide range of deficits known as fetal alcohol spectrum disorders (FASDs). Many factors determine vulnerability to developmental alcohol exposure including timing and pattern of exposure, nutrition and genetics. Here, we characterized how a prevalent single nucleotide polymorphism in the human brain-derived neurotrophic factor (BDNF) gene (val66met) modulates FASDs severity. This polymorphism disrupts BDNF's intracellular trafficking and activity-dependent secretion, and has been linked to increased incidence of neuropsychiatric disorders such as depression and anxiety. We hypothesized that developmental ethanol (EtOH) exposure more severely affects mice carrying this polymorphism. We used transgenic mice homozygous for either valine (BDNF(val/val) ) or methionine (BDNF(met/met) ) in residue 68, equivalent to residue 66 in humans. To model EtOH exposure during the second and third trimesters of human pregnancy, we exposed mice to EtOH in vapor chambers during gestational days 12 to 19 and postnatal days 2 to 9. We found that EtOH exposure reduces cell layer volume in the dentate gyrus and the CA1 hippocampal regions of BDNF(met/met) but not BDNF(val/val) mice during the juvenile period (postnatal day 15). During adulthood, EtOH exposure reduced anxiety-like behavior and disrupted trace fear conditioning in BDNF(met/met) mice, with most effects observed in males. EtOH exposure reduced adult neurogenesis only in the ventral hippocampus of BDNF(val/val) male mice. These studies show that the BDNF val66met polymorphism modulates, in a complex manner, the effects of developmental EtOH exposure, and identify a novel genetic risk factor that may regulate FASDs severity in humans. CI - (c) 2018 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society. FAU - Bird, C W AU - Bird CW AD - Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico. FAU - Baculis, B C AU - Baculis BC AD - Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico. FAU - Mayfield, J J AU - Mayfield JJ AD - Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico. FAU - Chavez, G J AU - Chavez GJ AD - Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico. FAU - Ontiveros, T AU - Ontiveros T AD - Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico. FAU - Paine, D J AU - Paine DJ AD - Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico. FAU - Marks, A J AU - Marks AJ AD - Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico. FAU - Gonzales, A L AU - Gonzales AL AD - Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico. FAU - Ron, D AU - Ron D AD - Department of Neurology, University of California, San Francisco, California. FAU - Valenzuela, C F AU - Valenzuela CF AUID- ORCID: 0000-0003-1026-9604 AD - Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico. LA - eng GR - R37 AA015614/AA/NIAAA NIH HHS/United States GR - R25 GM075149/GM/NIGMS NIH HHS/United States GR - P50 AA022534/AA/NIAAA NIH HHS/United States GR - R37 AA016848/AA/NIAAA NIH HHS/United States GR - P50 AA017072/AA/NIAAA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180528 PL - England TA - Genes Brain Behav JT - Genes, brain, and behavior JID - 101129617 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Central Nervous System Depressants) RN - 3K9958V90M (Ethanol) SB - IM MH - Animals MH - Anxiety/*genetics MH - Brain-Derived Neurotrophic Factor/*genetics MH - Central Nervous System Depressants/*toxicity MH - Conditioning, Classical MH - Ethanol/*toxicity MH - Fear MH - Female MH - Hippocampus/*drug effects/growth & development MH - Male MH - Mice MH - *Mutation, Missense MH - Polymorphism, Single Nucleotide MH - Pregnancy MH - Prenatal Exposure Delayed Effects/*genetics PMC - PMC6291361 MID - NIHMS999802 OTO - NOTNLM OT - anxiety OT - behavior OT - brain derived neurotrophic factor OT - development OT - elevated zero maze OT - ethanol OT - fetal alcohol OT - hippocampal volume OT - hippocampus OT - trace fear conditioning EDAT- 2018/04/25 06:00 MHDA- 2019/05/02 06:00 PMCR- 2020/03/01 CRDT- 2018/04/26 06:00 PHST- 2018/01/10 00:00 [received] PHST- 2018/04/03 00:00 [revised] PHST- 2018/04/18 00:00 [accepted] PHST- 2018/04/25 06:00 [pubmed] PHST- 2019/05/02 06:00 [medline] PHST- 2018/04/26 06:00 [entrez] PHST- 2020/03/01 00:00 [pmc-release] AID - 10.1111/gbb.12484 [doi] PST - ppublish SO - Genes Brain Behav. 2019 Mar;18(3):e12484. doi: 10.1111/gbb.12484. Epub 2018 May 28.