Autism spectrum disorder (ASD) has increased in incidence over the past several decades, and is associated with a range of co-morbidities including gastrointestinal (GI) dysfunctions including gastroesophageal reflux, abdominal pain, bloating, constipation and/or diarrhea. Several animal models have been used that replicate several aspects of ASD but no single model has been able to replicate the entire disease pathophysiology. In humans, prenatal exposure to valproic acid (VPA) has been identified as a significant risk factor and rodent models have shown that in utero VPA exposure leads to behavioral deficits in offspring. The present study aimed to investigate whether in utero exposure to VPA induces GI dysfunction in rats. Timed pregnant Sprague-Dawley rats were injected with a single dose of VPA at embryonic day 12.5. Both male and female offspring subsequently underwent behavioral studies and assessment of GI function in adulthood. In utero VPA treatment induced social deficits in both male and female offspring, decreasing sociability and social novelty. Histological examination showed that VPA treated offspring had decreased thickness of GI muscle and mucosa, while immunohistochemical studies showed a decrease in myenteric neuron number in the fundus. Functional studies showed that both male and female VPA offspring had a delay in gastric emptying compared to vehicle treated offspring. Results of the current study suggest that the rat VPA model of behavioral deficits may be a convenient model by which both mechanistic and functional insights into GI dysfunction may be studied.
Keywords: autism spectrum disorder; myenteric plexus; social deficit.
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