title: Importance of genetics in fetal alcohol effects: null mutation of the nNOS gene worsens alcohol-induced cerebellar neuronal losses and behavioral deficits.
abstract: The cerebellum is a major target of alcohol-induced damage in the developing brain. However, the cerebella of some children are much more seriously affected than others by prenatal alcohol exposure. As a consequence of in utero alcohol exposure, some children have substantial reductions in cerebellar volume and corresponding neurodevelopmental problems, including microencephaly, ataxia, and balance deficits, while other children who were exposed to similar alcohol quantities are spared. One factor that likely plays a key role in determining the impact of alcohol on the fetal cerebellum is genetics. However, no specific gene variant has yet been identified that worsens cerebellar function as a consequence of developmental alcohol exposure. Previous studies have revealed that mice carrying a homozygous mutation of the gene for neuronal nitric oxide synthase (nNOS-/- mice) have more severe acute alcohol-induced neuronal losses from the cerebellum than wild type mice. Therefore, the goals of this study were to determine whether alcohol induces more severe cerebellum-based behavioral deficits in nNOS-/- mice than in wild type mice and to determine whether these worsened behavior deficits are associated with worsened cerebellar neuronal losses. nNOS-/- mice and their wild type controls received alcohol (0.0, 2.2, or 4.4mg/g) daily over postnatal days 4-9. In adulthood, the mice underwent behavioral testing, followed by neuronal quantification. Alcohol caused dose-related deficits in rotarod and balance beam performance in both nNOS-/- and wild type mice. However, the alcohol-induced behavioral deficits were substantially worse in the nNOS-/- mice than in wild type. Likewise, alcohol exposure led to losses of Purkinje cells and cerebellar granule cells in mice of both genotypes, but the cell losses were more severe in the nNOS-/- mice than in wild type. Behavioral performances were correlated with neuronal number in the nNOS-/- mice, but not in wild type. Thus, homozygous mutation of the nNOS gene increases vulnerability to alcohol-induced cerebellar dysfunction and neuronal loss. nNOS is the first gene identified whose mutation worsens alcohol-induced cerebellar behavioral deficits.
authors.affiliation: Department of Biology, Wartburg College, Waverly, IA, United States.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Bonthius
authors.affiliation: Department of Pediatrics, University of Iowa College of Medicine, Iowa City, IA, United States.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Winters
authors.affiliation: Department of Pediatrics, University of Iowa College of Medicine, Iowa City, IA, United States.
authors.forename: Bahri
authors.initials: B
authors.lastname: Karacay
authors.affiliation: Department of Biology, Wartburg College, Waverly, IA, United States.
authors.forename: Samantha Larimer
authors.initials: SL
authors.lastname: Bousquet
authors.affiliation: Department of Pediatrics, University of Iowa College of Medicine, Iowa City, IA, United States; Department of Neurology, University of Iowa College of Medicine, Iowa City, IA, United States; Department of Neuroscience Program, University of Iowa College of Medicine, Iowa City, IA, United States. Electronic address: daniel-bonthius@uiowa.edu.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Bonthius
mesh_terms: D000438:Alcohols / Q000097:blood / Q000633:toxicity*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000187:drug effects; D002526:Cerebellar Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D001523:Mental Disorders / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000187:drug effects*; D052248:Nitric Oxide Synthase Type I / Q000172:deficiency* / Q000235:genetics; D009929:Organ Size / Q000187:drug effects / Q000235:genetics; D011597:Psychomotor Performance / Q000187:drug effects
chemical_list: D000438:Alcohols; D052248:Nitric Oxide Synthase Type I
keywords: Balance beam; Cell death; Granule cells; Microcephaly; Purkinje cells; Rotarod