VPA-induced apoptosis and behavioral deficits in neonatal mice

• Published in: Brain research Vol. 1203; pp. 126 - 132
• Main Authors: Yochum, Carrie L, Dowling, Peter, Reuhl, Kenneth R, Wagner, George C, Ming, Xue
• Format: Journal Article
• Language: English
• Published: London Elsevier B.V 08.04.2008; Amsterdam Elsevier; New York, NY
• Subjects: Analysis of Variance; Animals; Animals, Newborn; Anticonvulsants - toxicity; Anticonvulsants. Antiepileptics. Antiparkinson agents; Apoptosis; Apoptosis - drug effects; Autism; Behavior, Animal - drug effects; Behavioral Symptoms - chemically induced; Behavioral Symptoms - pathology; Biological and medical sciences; Brain - drug effects; Brain - pathology; Cell Count; Cerebellum; Child clinical studies; Developmental disorders; Female; In Situ Nick-End Labeling - methods; Infantile autism; Male; Medical sciences; Mice; Mice, Inbred BALB C; Motor Activity - drug effects; Neurology; Neuropharmacology; Pharmacology. Drug treatments; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Sex Factors; Social Behavior; Sodium valproate; Time Factors; Valproic Acid - toxicity; Cerebellum; Autism; Sodium valproate; Apoptosis; Rodentia; Central nervous system; Anticonvulsant; Developmental disorder; Valproic acid; Encephalon; Vertebrata; Mammalia; Sodium; Mouse; Cell death; Newborn animal; Animal; Behavior
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2008.01.055

Abstract Sodium valproate (VPA) administered to neonatal mice causes cognitive and motor deficits similar to those observed in humans with autism. In an effort to further evaluate similarities between early VPA exposure and autism, the present study examined treated mice for deficits in social behavior and neuronal damage. BALB/c mice injected on P14 with 400 mg/kg VPA engaged in fewer social interactions (including ano-genital sniffs, allogrooming, and crawl-under/over behaviors) than control mice. Treated mice also exhibited reduced motor activity in a social context but were not significantly different from controls when motor activity was assessed in non-social settings. A second set of BALB/c mice were treated with VPA on P14 and sacrificed at different times thereafter for histopathological analysis. At time-points 12 and 24 h following VPA, treated mice had up to a 30-fold increase in the number of TUNEL-positive cells in the external granule cell layer of the cerebellum and a 10-fold increase in TUNEL-positive cells in the dentate gyrus of the hippocampus. These observations may provide a histopathological correlate for the social deficits observed following post-natal VPA exposure and supports the use of early VPA administration as an animal model for the study of autism.