Postnatal brain myelination in an animal model of autism induced by prenatal exposure to valproic acid
Autism, Valproic acid, Myelin, Gene expression, Frontal cortex
Mammalian brain circuits are formed through the interaction between timely regulated genetic and environmental signals during neural development. These signals control synaptic formation, synaptic pruning and myelination, all processes that are required for maturation and establishment of the adult neural connectivity. In developmental disorders, such as autism spectrum disorders, deficits in these processes may lead to abnormal neural circuitry development and, in consequence, to physiological and behavioral alterations, including social deficits, restricted interests, stereotyped movements, sensory disturbances, and epileptic seizures. Recently, a transcriptome study from our lab indicate that infant VPA (valproic acid)-treated rats have altered expression of synaptic genes and reduced expression of myelin-related genes in the frontal cortex, suggesting possible molecular mechanisms for the behavioral deficits previously observed in these animals. Therefore, the aim of this study was to investigate the myelination pattern in the forebrain of VPA-treated rats at different postnatal ages (infant: P15, adolescent: P30 and adult: P60). For that, experimental and control groups were generated by injecting pregnant dams with 500 mg/Kg i.p. VPA or saline, respectively, on embryonic day 12.5 (E12.5). Analysis of myelin integrity was conducted by two different approaches: (1) histological quantification of the thickness and myelin staining intensity of the major forebrain white matter tracts (corpus callosum, anterior commissure, fimbria and internal/external capsule) using the myelin-specific stain Black Gold; and (2) gene expression analysis of myelin-related genes (Mobp, Plp1, Mag, and Klhl1) in dissected samples of the frontal cortex of P15 rats by quantitative real-time PCR.