Long-term valproic acid exposure increases the number of neocortical neurons in the developing rat brain. A possible new animal model of autism

• Published in: Neuroscience letters Vol. 580; pp. 12 - 16
• Main Authors: Sabers, Anne, Bertelsen, Freja C.B., Scheel-Krüger, Jørgen, Nyengaard, Jens R., Møller, Arne
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 19.09.2014
• Subjects: Animals; Anticonvulsants - adverse effects; Autism; Autistic Disorder - etiology; Autistic Disorder - pathology; Cell Count; Disease Models, Animal; Female; Lactation; Maternal Exposure; Neocortex - embryology; Neocortex - growth & development; Neocortex - pathology; Neurodevelopment; Neurons - pathology; Pregnancy; Prenatal Exposure Delayed Effects - etiology; Prenatal Exposure Delayed Effects - pathology; Psychotropic Drugs - adverse effects; Rats, Wistar; Teratogenesis; Valproate; Valproic acid; Valproic Acid - adverse effects; Teratogenesis; Pregnancy; Neurodevelopment; Autism; Valproic acid; Valproate
• ISSN: 0304-3940; 1872-7972
• DOI: 10.1016/j.neulet.2014.07.036

Valproic acid increases the number of neocortical neurons in the developing rat brain. •Fetal exposure of valproic acid interferes with normal brain development.•The neocortical organization is disturbed resulting in overgrowth of frontal lobes.•The neuronal overgrowth is induced even at relatively low doses of valproic acid.•Prenatal valproic acid may be a causative factor in autism spectrum disorders.•This model may provide a new translational model of human autism. The aim of this study was to test the hypothesis that long-term fetal valproic acid (VPA) exposure at doses relevant to the human clinic interferes with normal brain development. Pregnant rats were given intraperitoneal injections of VPA (20mg/kg or 100mg/kg) continuously during the last 9–12 days of pregnancy and during the lactation period until sacrifice on the 23rd postnatal day. Total number of neocortical neurons was estimated using the optical fractionator and frontal cortical thicknesses were sampled in VPA exposed pups compared with an unexposed control group. We found that pups exposed to 20mg/kg and 100mg/kg doses of VPA had statistically significant higher total number of neurons in neocortex by 15.8% and 12.3%, respectively (p<0.05) compared to controls amounting to 15.5×106 neocortical neurons (p<0.01). There was no statistical difference between the two VPA groups. Pups exposed to100mg/kg, but not to 20mg/kg VPA displayed a significant (p<0.05) broader (7.5%) of frontal cortical thickness compared to controls. Our results support the hypothesis that fetal exposure of VPA may interfere with normal brain development by disturbing neocortical organization, resulting in overgrowth of frontal lobes and increased neuronal cell numbers. The results indirectly suggest that prenatal VPA may contribute as a causative factor in the brain developmental disturbances equivalent to those seen in human autism spectrum disorders. We therefore suggest that this version of the VPA model may provide a translational model of autism.