Abnormal Enteric Nervous System Organization and Gastrointestinal Motility in Mice With Valproic Acid-Induced Neural Tube Defects.

backgroundNeural tube defects (NTDs) are a common congenital birth anomaly that can occur at either cranial levels, resulting in anencephaly, or spinal levels, resulting in spina bifida. Neurogenic bowel is a major cause of morbidity in patients affected by spina bifida, but it is unknown whether the gastrointestinal (GI) tract is affected in other types of NTDs. An absolute requirement for GI motility is the enteric nervous system (ENS) located within the walls of the GI tract. Enteric neurons coalesce into circumferential stripes throughout embryonic, fetal, and early postnatal development, and this gradual organization of the ENS into enteric neuronal stripes correlates with the emergence of neurogenic GI motility. We hypothesized that NTDs are associated with changes in ENS organization that correlate with specific GI motility defects.

methodsWe used prenatal valproic acid (VPA) exposure to induce exencephaly, a cranial NTD, in fetal mice. We used immunohistochemistry, high resolution confocal imaging, and ex vivo motility assays to assess enteric neuronal stripes and gastrointestinal motility in fetuses with a VPA-induced NTD. KEY

resultsGI tracts from fetuses with a VPA-induced NTD contain blood. Structurally, the enteric neuronal stripes are thinner with a narrower interstripe distance, leading to an increased number of stripes. Functionally, GI motility is abnormal, with increased contraction frequency and increased length of contractile segments. CONCLUSIONS AND INFERENCES: ENS organization and GI motility are disrupted in mouse fetuses with a VPA-induced NTD. This has important implications for our understanding of neurogenic bowel in central nervous system diseases such as spina bifida.