| dc.description.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. | |
