title: Chronic treatment with valproic acid or sodium butyrate attenuates novel object recognition deficits and hippocampal dendritic spine loss in a mouse model of autism.
abstract: We recently showed that prenatal exposure to valproic acid (VPA) in mice causes autism-like behavioral abnormalities, including social interaction deficits, anxiety-like behavior and spatial learning disability, in male offspring. In the present study, we examined the effect of prenatal VPA on cognitive function and whether the effect is improved by chronic treatment with VPA and sodium butyrate, histone deacetylase inhibitors. In addition, we examined whether the cognitive dysfunction is associated with hippocampal dendritic morphological changes. Mice given prenatal exposure to VPA exhibited novel object recognition deficits at 9 weeks of age, and that the impairment was blocked by chronic (5-week) treatment with VPA (30 mg/kg/d, i.p.) or sodium butyrate (1.2g/kg/d, i.p.) starting at 4 weeks of age. In agreement with the behavioral findings, the mice prenatally exposed to VPA showed a decrease in dendritic spine density in the hippocampal CA1 region, and the spine loss was attenuated by chronic treatment with sodium butyrate or VPA. Furthermore, acute treatment with sodium butyrate, but not VPA, significantly increased acetylation of histone H3 in the hippocampus at 30 min, suggesting the difference in the mechanism for the effects of chronic VPA and sodium butyrate. These findings suggest that prenatal VPA-induced cognitive dysfunction is associated with changes in hippocampal dendritic spine morphology.
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takuma
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Hara
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kataoka
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Kawanai
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Maeda
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Watanabe
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Erika
authors.initials: E
authors.lastname: Takano
authors.affiliation: United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Hayata-Takano
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan; United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hashimoto
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ago
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan; United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan. Electronic address: matsuda@phs.osaka-u.ac.jp.
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsuda
mesh_terms: D000107:Acetylation; D000818:Animals; D001321:Autistic Disorder / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology; D020148:Butyric Acid / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D056547:CA1 Region, Hippocampal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D049229:Dendritic Spines / Q000187:drug effects* / Q000473:pathology; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects*; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D008297:Male; D051379:Mice; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000517:prevention & control; D014635:Valproic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D020148:Butyric Acid; D014635:Valproic Acid
keywords: Autism spectrum disorders; Dendritic spines; Hippocampus; Histone deacetylase; Sodium butyrate; Valproic acid