Analysis of the central nervous system in a mouse model of HSAN Type III
Waller, Hannah Rose
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Familial Dysautonomia (FD), also called Riley Day Syndrome, is a Hereditary Sensory and Autonomic Neuropathy (HSAN Type III) that is characterized by dysfunction of the sensory and autonomic nervous systems. The disease is caused by a severe reduction in levels of the protein IKAP as a result of a point mutation in Ikbkap mRNA which results in targeting of the mRNA for nonsense mediated decay. In humans, symptoms include autonomic crises, tachycardia, blood pressure lability, lack of overflow tears, decreased pain and temperature sensation, and scoliosis. Half of affected individuals die by age 40. Although FD has been traditionally classified as a disease of the autonomic nervous system, there have been notable effects observed in the central nervous system (CNS) as well, though many of these observations remain to be quantified. The presented study evaluated the impact of FD on the CNS using a mouse model where Ikbkap was deleted selectively from neurons of the CNS. For this model, a conditional knockout (CKO) strategy was employed because mice that are null for Ikbkap die by embryonic day 10.5, precluding their usefulness for analyzing FD in the adult CNS. For this study, morphological analyses and immunohistochemical staining were performed on the brain tissue. Affected mice were found to have a significant reduction in choline acetyltransferase (ChAT) positive neurons in the dorsal motor nucleus of the vagus nerve (DMNX) relative to controls, indicating potential decreased parasympathetic innervation of the nucleus in the heart and other target organs. Additionally, the size of the lateral ventricles and hippocampus relative to hemisphere size was significantly increased for the mutant mice. Further, the corpus callosum and lateral amygdaloid nucleus areas were significantly decreased relative to wild-type controls. Cortical layering was found to be normal in Talpha1tubulin-Cre/Ikbkap CKO mice. Taken together, these results suggest that the morphological differences are associated with increased cell death and decreased neurogenesis and cell differentiation. The neural and morphological findings presented in this study are the first data demonstrating perturbations in the CNS of a mouse model for FD and may explain some of the phenotypes observed in FD patients.