Autism spectrum disorders (ASD) involve a complex interplay of both genetic and environmental risk factors, such as prenatal exposure to valproic acid (VPA). Considering the neuroprotective, antioxidant and anti-inflammatory effects of resveratrol (RSV), we investigated the influence of prenatal RSV treatment on social behaviors of a rodent model of autism induced by prenatal exposure to VPA. In the three-chambered apparatus test, the VPA group showed a reduced place preference conditioned by conspecific and no preference between exploring a wire-cage or a rat enclosed inside a wire cage, revealing sociability impairments. Prenatal administration of RSV prevented the VPA-induced social impairments evaluated in this study. A bioinformatics analysis was used to discard possible molecular interactions between VPA and RSV during administration. The interaction energy between RSV and VPA is weak and highly unstable, suggesting cellular effects instead of a single chemical process. In summary, the present study highlights a promising experimental strategy to evaluate new molecular targets possibly involved in the etiology of autism and developmental alterations implicated in neural and behavioral impairments in ASD.

Autism spectrum disorder (ASD) is characterized by impairments in both social communication and interaction and repetitive or stereotyped behaviors. Although its etiology remains unknown, genetic and environmental risk factors have been associated with this disorder, including the exposure to valproic acid (VPA) during pregnancy. Resveratrol (RSV) is an anti-inflammatory and antioxidant molecule known to prevent social impairments in the VPA animal model of autism. This study aimed to analyze the effects of prenatal exposure to VPA, as well as possible preventive effects of RSV, on sensory behavior, the localization of GABAergic parvalbumin (PV+) neurons in sensory brain regions and the expression of proteins of excitatory and inhibitory synapses. Pregnant rats were treated daily with RSV (3.6 mg/kg) from E6.5 to E18.5 and injected with VPA (600 mg/kg) in the E12.5. Male pups were analyzed in Nest Seeking (NS) behavior and in whisker nuisance task (WNT). At P30, the tissues were removed and analyzed by immunofluorescence and western blotting. Our data showed for the first time an altered localization of PV+-neurons in primary sensory cortex and amygdala. We also showed a reduced level of gephyrin in the primary somatosensory area (PSSA) of VPA animals. The treatment with RSV prevented all the aforementioned alterations triggered by VPA. Our data shed light on the relevance of sensory component in ASD and highlights the interplay between RSV and VPA animal model as an important tool to investigate the pathophysiology of ASD.

Autism spectrum disorder (ASD) is characterized by difficulties in social interaction, communication and language, and restricted repertoire of activities and interests. The etiology of ASD remains unknown and no clinical markers for diagnosis were identified. Environmental factors, including prenatal exposure to valproic acid (VPA), may contribute to increased risk of developing ASD. MicroRNA (miRNA) are small noncoding RNA that regulate gene expression and are frequently linked to biological processes affected in neurodevelopmental disorders. In this work, we analyzed the effects of resveratrol (an antioxidant and anti-inflammatory molecule) on behavioral alterations of the VPA model of autism, as well as the levels of circulating miRNA. We also evaluated the same set of miRNA in autistic patients. Rats of the VPA model of autism showed reduced total reciprocal social interaction, prevented by prenatal treatment with resveratrol (RSV). The levels of miR134-5p and miR138-5p increased in autistic patients. Interestingly, miR134-5p is also upregulated in animals of the VPA model, which is prevented by RSV. In conclusion, our findings revealed important preventive actions of RSV in the VPA model, ranging from behavior to molecular alterations. Further evaluation of preventive mechanisms of RSV can shed light in important biomarkers and etiological triggers of ASD.

Impairments in social behaviour are a defining feature of autism spectrum disorder (ASD).Individuals with ASD also usually present some difficulty to recognise or understand another person's feelings. Therefore, it is possible that altered empathy processing could hinder typical social interaction in ASD. Recently, robust paradigms confirmed that rodents show primordial forms of empathy-like behaviour. Therefore, in this work, we used one of these new protocols to test pro-social behaviour in the rat model of autism induced by Valproic Acid (VPA). We also evaluated possible beneficial effects of Resveratrol, since it can prevent social deficits in the VPA model. Rats were tested on their ability to open a restrainer to release a trapped conspecific. Exposure to VPA precludes the timely manifestation of this empathy-like behaviour, but does not affect its continuation after its first expression. We also found a significant correlation between average speed during the first day of test and becoming an Opener. Similarly, rats able to open the restrainer on the first day had an increased likelihood of repeating this behaviour in the later days of the testing programme. We did not find any protective effects of Resveratrol. Further investigation of empathy-like behaviour in the VPA model and in other models of autism could help to clarify the behavioural and neural processes underpinning the basic aspects of empathy alterations in autistic individuals.

Autism spectrum disorder (ASD) is a highly prevalent developmental disorder characterized by deficits in communication and social interaction and in stereotyped or repetitive behaviors. Besides the classical behavioral dyad, several comorbidities are frequently present in patients with ASD, such as anxiety, epilepsy, sleep disturbances, and gastrointestinal tract dysfunction. Although the etiology of ASD remains unclear, there is supporting evidence for the involvement of both genetic and environmental factors. Valproic acid (VPA) is an anticonvulsant and mood stabilizer that, when used during the gestational period, increases the risk of ASD in the offspring. The animal model of autism induced by prenatal exposure to VPA demonstrates important structural and behavioral features that can be observed in individuals with autism; it is thus an excellent tool for testing new drug targets and developing novel behavioral and drug therapies. In addition, immunological alterations during pregnancy could affect the developing embryo because immune molecules can pass through the placental barrier. In fact, exposure to pathogens during the pregnancy is a known risk factor for ASD, and maternal immune activation can lead to autistic-like features in animals. Interestingly, neuroimmune alterations are common in both autistic individuals and in animal models of ASD. We summarize here the important alterations in inflammatory markers, such as cytokines and chemokines, in patients with ASD and in the VPA animal model.

Neurodevelopmental disorders (NDDs) are a heterogeneous and highly prevalent group of psychiatric conditions marked by impairments in the nervous system. Their onset occurs during gestation, and the alterations are observed throughout the postnatal life. Although many genetic and environmental risk factors have been described in this context, the interactions between them challenge the understanding of the pathways associated with NDDs. Transcription factors (TFs)—a group of over 1,600 proteins that can interact with DNA, regulating gene expression through modulation of RNA synthesis—represent a point of convergence for different risk factors. In addition, TFs organize critical processes like angiogenesis, blood‐brain barrier formation, myelination, neuronal migration, immune activation, and many others in a time and location‐dependent way. In this review, we summarize important TF alterations in NDD and associated disorders, along with specific impairments observed in animal models, and, finally, establish hypotheses to explain how these proteins may be critical mediators in the context of genome‐environment interactions.

Autism spectrum disorder (ASD) is characterized by deficits in communication and social interaction, restricted interests, and stereotyped behavior. Environmental factors, such as prenatal exposure to valproic acid (VPA), may contribute to the increased risk of ASD. Since disturbed functioning of the purinergic system has been associated with the onset of ASD and used as a potential therapeutic target for ASD in both clinical and preclinical studies, we analyzed the effects of suramin, a nonselective purinergic antagonist, on behavioral, molecular and immunological in an animal model of autism induced by prenatal exposure to VPA. Treatment with suramin (20 mg/Kg, intraperitoneal) restored sociability in the three-chamber apparatus and decreased anxiety measured by elevated plus maze apparatus, but had no impact on decreased reciprocal social interactions or higher nociceptive threshold in VPA rats. Suramin treatment had no impact on VPA-induced upregulation of P2X4 and P2Y2 in hippocampus, and P2X4 in medial prefrontal cortex, but normalized an increased level of interleukin 6 (IL-6). Our results suggest an important role of purinergic modulation in behavioral, molecular, and immunological aberrations described in VPA model, and suggest that purinergic system might be a potential target for pharmacotherapy in preclinical studies of ASD.

Autism spectrum disorder can present a plethora of clinical conditions associated with the disorder, such as greater brain volume in the first years of life in a significant percentage of patients. We aimed to evaluate the brain water content, the blood–brain barrier permeability, and the expression of aquaporin 1 and 4, and GFAP in a valproic acid‐animal model, assessing the effect of resveratrol. On postnatal day 30, Wistar rats of the valproic acid group showed greater permeability of the blood–brain barrier to the Evans blue dye and a higher proportion of brain water volume, prevented both by resveratrol. Prenatal exposition to valproic acid diminished aquaporin 1 in the choroid plexus, in the primary somatosensory area, in the amygdala region, and in the medial prefrontal cortex, reduced aquaporin 4 in medial prefrontal cortex and increased aquaporin 4 levels in primary somatosensory area (with resveratrol prevention). Valproic acid exposition also increased the number of astrocytes and GFAP fluorescence in both primary somatosensory area and medial prefrontal cortex. In medial prefrontal cortex, resveratrol prevented the increased fluorescence. Finally, there was an effect of resveratrol per se on the number of astrocytes and GFAP fluorescence in the amygdala region and in the hippocampus. Thus, this work demonstrates significant changes in blood–brain barrier permeability, edema formation, distribution of aquaporin 1 and 4, in addition to astrocytes profile in the animal model of autism, as well as the use of resveratrol as a tool to investigate the mechanisms involved in the pathophysiology of autism spectrum disorder.