Environmental enrichment attenuates behavioral abnormalities in valproic acid-exposed autism model mice

• Published in: Behavioural brain research 2017-08, Vol.333, p.67-73
• Main Authors: Yamaguchi, Hiroshi, Hara, Yuta, Ago, Yukio, Takano, Erika, Hasebe, Shigeru, Nakazawa, Takanobu, Hashimoto, Hitoshi, Matsuda, Toshio, Takuma, Kazuhiro
• Format: Article
• Language: English
• Subjects: Animals; Anticonvulsants - toxicity; Autism; Autistic Disorder - chemically induced; Autistic Disorder - complications; Behavioral abnormalities; Brain - cytology; Brain - pathology; Brain-Derived Neurotrophic Factor - genetics; Brain-Derived Neurotrophic Factor - metabolism; Dendritic spines; Dendritic Spines - drug effects; Dendritic Spines - pathology; Dendritic Spines - ultrastructure; Disease Models, Animal; Disks Large Homolog 4 Protein - genetics; Disks Large Homolog 4 Protein - metabolism; Environment; Environmental enrichment; Exploratory Behavior - drug effects; Female; Gene Expression Regulation - drug effects; Interpersonal Relations; Male; Maze Learning - drug effects; Mental Disorders - etiology; Mental Disorders - nursing; Mental Disorders - pathology; Mice; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Pregnancy; Prenatal Exposure Delayed Effects - chemically induced; Prenatal Exposure Delayed Effects - physiopathology; Valproic acid; Valproic Acid - toxicity
• ISSN: 0166-4328; 1872-7549
• DOI: 10.1016/j.bbr.2017.06.035

•Environmental enrichment attenuates ASD-like phenotypes in the VPA model of autism.•Environmental enrichment repaired hippocampal dendritic spine loss.•Environmental enrichment increased mRNA levels of PSD-95 and Shank2.•Improvement of ASD-like behaviors may be mediated by enhancing synaptic function. We recently demonstrated that prenatal exposure to valproic acid (VPA) at embryonic day 12.5 causes autism spectrum disorder (ASD)-like phenotypes such as hypolocomotion, anxiety-like behavior, social deficits and cognitive impairment in mice and that it decreases dendritic spine density in the hippocampal CA1 region. Previous studies show that some abnormal behaviors are improved by environmental enrichment in ASD rodent models, but it is not known whether environmental enrichment improves cognitive impairment. In the present study, we examined the effects of early environmental enrichment on behavioral abnormalities and neuromorphological changes in prenatal VPA-treated mice. We also examined the role of dendritic spine formation and synaptic protein expression in the hippocampus. Mice were housed for 4 weeks from 4 weeks of age under either a standard or enriched environment. Enriched housing was found to increase hippocampal brain-derived neurotrophic factor mRNA levels in both control and VPA-exposed mice. Furthermore, in VPA-treated mice, the environmental enrichment improved anxiety-like behavior, social deficits and cognitive impairment, but not hypolocomotion. Prenatal VPA treatment caused loss of dendritic spines in the hippocampal CA1 region and decreases in mRNA levels of postsynaptic density protein-95 and SH3 and multiple ankyrin repeat domains 2 in the hippocampus. These hippocampal changes were improved by the enriched housing. These findings suggest that the environmental enrichment improved most ASD-like behaviors including cognitive impairment in the VPA-treated mice by enhancing dendritic spine function.