Abstract
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.
Highlights
Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental condition affecting 1 in 68 children aged 8 years in the USA (American Psychiatry Association (APA), 2013) and is characterized, according to the DSM-5, by a behavioral dyad composed by impairments in communication and social interaction and repetitive or stereotyped behaviors (American Psychiatry Association (APA), 2013)
In order to evaluate the effects of valproic acid (VPA) and RSV on olfactory discrimination, postnatal day 10 (P10) pups were tested for Nest Seeking (NS) behavior (Figure 1A)
We report in our present work that RSV reestablishes the typical proportion of GABAergic PV+-neurons in the amygdala of VPA animals, which might be crucial for proper inhibition of responses in the amygdala (McDonald and Betette, 2001; Woodruff and Sah, 2007; Bocchio et al, 2015)
Summary
Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental condition affecting 1 in 68 children aged 8 years in the USA (American Psychiatry Association (APA), 2013) and is characterized, according to the DSM-5, by a behavioral dyad composed by impairments in communication and social interaction and repetitive or stereotyped behaviors (American Psychiatry Association (APA), 2013). Many interesting theories have been recently proposed (Patterson, 2009; Lucchina and Depino, 2013; Sandin et al, 2014; Gottfried et al, 2015), the ASD etiology remains unknown. Some environmental factors are associated to ASD, including prenatal exposure to valproic acid (VPA; Rodier et al, 1997; Christensen et al, 2013; Smith and Brown, 2014). Based on these clinical observations, an animal model of autism by prenatal exposure to VPA was developed. It has been extensively validated, demonstrating a myriad of behavioral (Schneider and Przewłocki, 2005; Haddad et al, 2009; Dendrinos et al, 2011; Favre et al, 2013; Gottfried et al, 2013; Roullet et al, 2013; Mabunga et al, 2015), molecular (Roullet et al, 2010; Gottfried et al, 2013), morphological (Rodier et al, 1997; Dendrinos et al, 2011; Favre et al, 2013; Gottfried et al, 2013) and electrophysiological autistic-like features (Dawson et al, 2005; Markram et al, 2008; Rinaldi et al, 2008)
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