Resveratrol Prevents Sensory Deficits in Animal Model of Autism Induced By Prenatal Exposure to VPA

Background:  Autism spectrum disorder (ASD) is classified as a neurodevelopmental disorder, presenting impairments in social communication and sociability, as well as stereotyped behavioral patterns. Although the etiology remains unknown, there is growing evidence suggesting a complex interplay between genetic and environmental risk factors during pregnancy. Many CNS impairments are related to ASD (e.g. multisensory alterations) and recent data were pointing out to an unbalance between excitation and inhibition with high predominance in excitation compound, particularly in cortical and limbic areas related to sensory processing. Prenatal exposure to valproic acid (VPA) is an environmental risk factor to ASD development and it has been widely used to induce autistic-like behaviors in rodents. We previously showed that a prenatal treatment with resveratrol (RSV) was able to prevent the social deficits induced by VPA in male offspring rats.

Objectives:  The present work aimed to investigate the effects of prenatal exposure to RSV and VPA in rats’ sensory behaviors.  In addition, we aimed to evaluate the gene expression of key synaptic components for the excitatory and inhibitory balance in the amygdala region. 

Methods:  Female rats were treated at 12.5 days of pregnancy, with VPA (600 mg/kg, i.p.) or vehicle. A low dose of RSV (3.6 mg/kg, s.c.) were administered from E6.5 to E18.5. Male pups from different litters of experimental groups were used for behavioral and molecular experiments. Two sensory behaviors were performed, at PN10 (Nest Seeking Behavior) and PN30 (Whisker Nuisance Task). After 30 days, male rats were euthanized and the relative gene expressions for synaptic proteins were evaluated. All data were analyzed by SPSS statistical program applying one-way ANOVA followed by Tukey’s test.  

Results:  Regarding the nest seeking behavioral test, VPA group presented reduced number of correct choices to the nest, which is in accordance to the literature data. RSV was able to prevent this behavioral impairment (in RSV+VPA group). However, the time to reach any shavings was increased in both VPA and RSV+VPA group. The WNT showed the same pattern of prevention by prenatal administration of RSV. The VPA group presented higher score values (higher nuisance) compared to RSV and RSV+VPA groups. Therefore, the prenatal treatment with RSV was capable to reduce the score values when compared to VPA group. The present work showed for the first time, significant alterations at the genic expression of synaptic proteins related to excitatory and inhibitory synapses in the amygdala region, an important brain structure related to attachment behavior and emotional features in sensory processing integration, known to be altered in ASD. RSV increased the genetic expression level of Gephyrin in the amygdala of RSV group. Also, RSV decreased the genetic expression levels of Synaptophysin in RSV+VPA group. There were no changes in genetic expression of PSD95 among groups.

Conclusions:  These data highlights RSV as an important preventive molecule in the study of autistic-like sensory behaviors in VPA model, as well as an important tool for seeking etiological targets and physiopathology studies in TEA.