title: Genetic absence of nNOS worsens fetal alcohol effects in mice. II: microencephaly and neuronal losses.
abstract: BACKGROUND
  Prenatal alcohol exposure can kill developing neurons, leading to microencephaly and mental retardation. However, not all fetuses are equally vulnerable to alcohol's neurotoxic effects. While some fetuses are severely affected and are ultimately diagnosed with fetal alcohol syndrome (FAS), others have no evidence of neuropathology and are behaviorally normal. These widely different outcomes among alcohol-exposed fetuses are likely due, in part, to genetic differences. Some fetuses possess genotypes that make them much more vulnerable than others to alcohol's teratogenic effects. However, to date, only 1 gene has been identified whose mutation can worsen alcohol-induced behavioral deficits in an animal model of FAS. That gene is neuronal nitric oxide synthase (nNOS). The purpose of this study was to determine whether mutation of nNOS can likewise worsen alcohol-induced microencephaly and lead to permanent neuronal deficits.
  
  
  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; the results of which are reported in the companion paper. The brains were then weighed, and stereological cell counts were performed on the cerebral cortex and hippocampal formation, which are the brain regions that mediate the aforementioned behavioral tasks.
  
  
  RESULTS
  Alcohol caused dose-dependent microencephaly, but only in the nNOS(-/-) mice and not in wild-type mice. Alcohol-induced neuronal losses were more severe in the nNOS(-/-) mice than in the wild-type mice in all of the brain regions examined, including the cerebral cortex, hippocampal CA3 subregion, hippocampal CA1 subregion, and dentate gyrus.
  
  
  CONCLUSIONS
  Targeted mutation of the nNOS gene increases the vulnerability of the developing brain to alcohol-induced growth restriction and neuronal losses. This increased neuropathology is associated with worsened behavioral dysfunction. The results demonstrate the critical importance of genotype in determining the outcome of developmental alcohol exposure.
authors: Department of Pediatrics , University of Iowa College of Medicine, Iowa City, Iowa.
authors: Bahri
authors: B
authors: Karacay
authors: Jo
authors: J
authors: Mahoney
authors: Jeffrey
authors: J
authors: Plume
authors: Daniel J
authors: DJ
authors: Bonthius
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000254:growth & development; D002452:Cell Count; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development; D004195:Disease Models, Animal; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000235:genetics* / Q000503:physiopathology; D059647:Gene-Environment Interaction; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D052248:Nitric Oxide Synthase Type I / Q000235:genetics*; D009929:Organ Size / Q000187:drug effects / Q000235:genetics; D011247:Pregnancy
chemical_list: D002492:Central Nervous System Depressants; D000431:Ethanol; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse
keywords: Cerebral Cortex; Dentate Gyrus; FASD; Hippocampus; Stereology