title: Embryological exposure to valproic acid disrupts morphology of the deep cerebellar nuclei in a sexually dimorphic way.
abstract: Autism spectrum disorders (ASD) is diagnosed in males at a much higher rate than females. For this reason, the majority of autism research has used male subjects exclusively. However; more recent studies using genetic sex as a factor find that the development of the male and female brain is differentially affected by ASD. That is, the natural sex-specific differences that exist between male and female brains lead to sexually dimorphic expressions of autism. Here we investigate the putative sexual dimorphism that exists in the deep cerebellar nuclei of male and female rats exposed to valproic acid (VPA) on embryological day 12.5. We find natural sex-specific differences in adult nucleus area, length, and estimated cell populations. Therefore VPA exposure during embryology creates some sex-specific deficits such as higher cell counts in the VPA males and lower cell counts in the VPA females. At the same time, some effects of VPA exposure occur regardless of sex. That is, smaller nucleus area and length lead to truncated nuclei in both VPA males and females. These deficits are more pronounced in the VPA males suggesting that genetic sex could play a role in teratogenic susceptibility to VPA. Taken together our results suggests that VPA exposure induces sexually dimorphic aberrations in morphological development along a mediolateral gradient at a discrete region of the hindbrain approximate to rhombomere (R) 1 and 2. Sex-specific disruption of the local and long-range projections emanating from this locus of susceptibility could offer a parsimonious explanation for the brain-wide neuroanatomical variance reported in males and females with ASD.
authors.affiliation: Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, United States. Electronic address: tm106@nyu.edu.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Mowery
authors.affiliation: Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, United States.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Wilson
authors.affiliation: Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, United States.
authors.forename: Polina V
authors.initials: PV
authors.lastname: Kostylev
authors.affiliation: Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, United States.
authors.forename: Blair
authors.initials: B
authors.lastname: Dina
authors.affiliation: Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, United States.
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Buchholz
authors.affiliation: Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, United States; Program in Neuroscience, Indiana University, Bloomington, IN, United States.
authors.forename: Anne L
authors.initials: AL
authors.lastname: Prieto
authors.affiliation: Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, United States; Program in Neuroscience, Indiana University, Bloomington, IN, United States.
authors.forename: Preston E
authors.initials: PE
authors.lastname: Garraghty
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D016022:Case-Control Studies; D002452:Cell Count; D002529:Cerebellar Nuclei / Q000187:drug effects / Q000473:pathology*; D002659:Child Development Disorders, Pervasive / Q000139:chemically induced* / Q000473:pathology*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005260:Female; D008297:Male; D051381:Rats; D020318:Rats, Long-Evans; D012727:Sex Characteristics; D014635:Valproic Acid / Q000633:toxicity*
chemical_list: D004791:Enzyme Inhibitors; D014635:Valproic Acid
keywords: Anti-epileptic compound; Autism spectrum disorder; Deep cerebellar nuclei; Sexual dimorphism