Abstract
Autism is a neurodevelopmental condition diagnosed by impaired social interaction, abnormal communication and, stereotyped behaviors. While post-mortem and imaging studies have provided good insights into the neurobiological symptomology of autism, animal models can be used to study the neuroanatomical, neurophysiological and molecular mediators in more detail and in a more controlled environment. The valproic acid (VPA) rat model is an environmentally triggered model with strong construct and clinical validity. It is based on VPA teratogenicity in humans, where mothers who are medicated with VPA during early pregnancy show an increased risk for giving birth to an autistic child. In rats, early embryonic exposure, around the time of neural tube closure, leads to autism-like anatomical and behavioral abnormalities in the offspring. Considering the increasing use of the VPA rat model, we present our observations of the general health of Wistar dams treated with a single intraperitoneal injection of 500 or, 600 mg/kg VPA on embryonic day E12.5, as well as their male and female offspring, in comparison to saline-exposed controls. We report increased rates of complete fetal reabsorption after both VPA doses. VPA 500 mg/kg showed no effect on dam body weight during pregnancy or, on litter size. Offspring exposed to VPA 500 mg/kg showed smaller brain mass on postnatal days 1 (P1) and 14 (P14), in addition to abnormal nest seeking behavior at P10 in the olfactory discrimination test, relative to controls. We also report increased rates of physical malformations in the offspring, rare occurrences of chromodacryorrhea and, developmentally similar body mass gain. Further documentation of developmental health may guide sub-grouping of individuals in a way to better predict core symptom severity.
Highlights
Autism is a severe and pervasive neurodevelopmental disorder, diagnosed by the age of 3 upon clinical presentation of impaired social interaction, abnormal communication, and repetitive behaviors
Considering the increasing use of the valproic acid (VPA) rat model, we present our observations of the general health of Wistar dams treated with a single intraperitoneal injection of 500 or, 600 mg/kg VPA on embryonic day E12.5, as well as their male and female offspring, in comparison to saline-exposed controls
The literature today demonstrates that VPA exposure in rodents at a specific time in embryonic development, is sufficient to induce neurodevelopmental and morphological features that resemble autism in humans
Summary
Autism is a severe and pervasive neurodevelopmental disorder, diagnosed by the age of 3 upon clinical presentation of impaired social interaction, abnormal communication, and repetitive behaviors. Autism is highly heritable (Sullivan et al, 2012), and many gene loci serve as potent risk factors (Bonora et al in Moldin and Rubenstein, 2006; Betancur, 2011; Matsunami et al, 2013). Environmental factors seem to play an increasingly important role, as indicated by prevalence estimates over the last 2 decades that rose from as low as 7 to as high as 72.6 cases per 10,000 (Fombonne, 2009). In support of the role of the environment in autism is the accumulated evidence that biochemical insults during early embryogenesis increase the risk for autistic symptoms in the child. Genetic and environmental factors seem to interact in biologically complex mechanisms to yield the broad heterogeneity in symptom severities (Zahir and Brown, 2011)
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