title: Genetic absence of nNOS worsens fetal alcohol effects in mice. I: behavioral deficits.
abstract: BACKGROUND
  Alcohol abuse during pregnancy often induces neuropsychological problems in the offspring, including learning disorders, attention deficits, and behavior problems, all of which are prominent components of fetal alcohol spectrum disorders (FASD). However, not all children who were exposed to alcohol in utero are equally affected by it. While some children have major deficits, others are spared. This unequal vulnerability is likely due largely to differences in fetal genetics. Some fetuses appear to have certain genotypes that make them much more prone to FASD. However, to date, no gene has been identified that worsens alcohol-induced brain dysfunction. Nitric oxide (NO) is a gaseous molecule that can protect developing neurons against alcohol-induced death. In the brain, NO is produced by neuronal nitric oxide synthase (nNOS). In this study, we examined whether homozygous mutation of the nNOS gene in mice worsens the behavioral deficits of developmental alcohol exposure.
  
  
  METHODS
  Wild-type and nNOS(-/-) mice received alcohol (0.0, 2.2, or 4.4 mg/g) daily over postnatal days (PDs) 4 to 9. Beginning on PD 85, the mice underwent a series of behavioral tests, including open field activity, the Morris water maze, and paired pulse inhibition.
  
  
  RESULTS
  For the wild-type mice, alcohol impaired performance only in the water maze. In contrast, for the nNOS(-/-) mice, alcohol impaired performance on all 3 tasks. Furthermore, the nNOS(-/-) mice were substantially more impaired than wild-type mice in their performance on all 3 of the behavioral tests and at both the low (2.2) and high (4.4) doses of alcohol.
  
  
  CONCLUSIONS
  Targeted disruption of the nNOS gene worsens the behavioral impact of developmental alcohol exposure and allows alcohol-induced learning problems to emerge that are not seen in wild type. This is the first demonstration that a specific genotype can interact with alcohol to worsen functional brain deficits in an animal model of FASD.
authors: Department of Pediatrics, University of Iowa College of Medicine, Iowa City, Iowa.
authors: Bahri
authors: B
authors: Karacay
authors: Nancy E
authors: NE
authors: Bonthius
authors: Jeffrey
authors: J
authors: Plume
authors: Daniel J
authors: DJ
authors: Bonthius
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D004195:Disease Models, Animal; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000235:genetics* / Q000503:physiopathology; D059647:Gene-Environment Interaction; D018782:Maze Learning / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects* / Q000235:genetics; D052248:Nitric Oxide Synthase Type I / Q000235:genetics*; D011247:Pregnancy; D065808:Prepulse Inhibition / Q000187:drug effects* / Q000235:genetics; D011897:Random Allocation
chemical_list: D002492:Central Nervous System Depressants; D000431:Ethanol; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse
keywords: FASD; Forebrain; Morris Water Maze; Open Field Activity; Paired Pulse Inhibition