Herdabilidade do comportamento social e alterações na composição neuronal do córtex pré-frontal em um modelo animal de autismo

Abstract

Autism comprises a heterogeneous group of disorders characterized by sensory, motor, language and mainly social deficits in early childhood. Genetic, epigenetic and environmental factors are strongly involved in the predisposition to autism. Studies in animal models of the disease suggest that these same factors can alter the development of the central nervous system, modifying patterns of differentiation and neuronal maturation and generating a dysfunctional brain circuitry. Our group previously characterized the animal model induced by administration of VPA in pregnant rats. We demonstrated that VPA-exposed animals during pregnancy (F1VPA) exhibit "autistic" behaviors in postnatal life, such as hyperlocomotion, prolonged stereotypy, and reduced social interaction. Histologically, we detected a reduction in the number of parvalbumin (PV)+ interneurons in the medial prefrontal cortex (mPFC) of these animals compared to controls. Considering the effects of VPA on chromatin structure and DNA methylation, we hypothesized that behavioral and histological changes observed in F1VPA animals would be transmissible for the next generation, independent of new VPA exposures. In this work, we analyzed the behavior and histology of mPFC in F1VPA progeny, hereafter referred to as F2. We observed that these animals present a significant reduction in social interaction and in the frequency of exploratory surveys when compared to control animals. This reduction in social preference, however, was intermediate between that presented by control animals and F1VPA animals, and in the latter the losses in social behavior were more intense. On the other hand, we did not observe hyperlocomotion, nor alterations in the exploratory behavior or stereotyped patterns in F2 animals when compared to the controls, once their profiles were normalized with respect to F1VPA animals. In order to test whether behavioral impairments in F2 stemmed from differences in parental care of VPA mothers and control mothers on their offspring, we performed cross-fostering experiments. We observed that F2 animals cared for by control mothers presented low rates of sociability when compared to control animals cared for by control mothers, which corroborates the interpretation that the observed changes in F2 animals are due to parental inherance. Histological evaluation of cortical tissue reveals changes in the proportion of PV+ interneurons in the mPFC of F1VPA animals. We also observed a slight increase in the total number of neurons in the CPFm of both F1VPA and F2 animals, suggesting that distinct alterations in the organization of neuronal circuitry may be present in both groups of animals. Therefore, our data indicate that prenatal exposure to VPA induces behavioral and histological changes in rats, and that these can be partially transmitted to their offspring. However, we cannot establish a direct correlation between social deficits and cellular changes in the mPFC, demonstrating that different changes in the circuitry can produce the same behavioral effects. This model may contribute in the future to the identification of genetic signatures associated with the behavioral and histological changes observed in autism.