NZB and BXSB strains of mice develop a variety of autoimmune syndromes and developmental neuropathology similar to that seen in dyslexic brains. These mice serve as an excellent murine model to study the relationship between autoimmunity and developmental neuropathology. If brain changes and disordered immunological regulation are causally related, the association could result from genetic issues directly affecting the immune and nervous systems of the fetus or epigenetic interactions between mother and fetus in the uterine and postnatal environment. If epigenetic, maternal immune factors aer suspect because the fetal immune system is not mature when the developmental brain changes originate. Several examples of fetal organ injury by transplacental passage of pathogenic autoantibodies from autoimmune mothers have been documented, and such a mechanism is likely to contribute to the genesis of fetal brain injury. The central hypothesis of the present proposal is to determine the relationship of epigenetic influences, e.g., maternally derived autoantibodies, with developmental cerebrocortical microdysgenesis in relevant murine models. To address this issue, three different strategies are proposed: (1) Embryo Transfer Studies - to test whether the development of DBA/2 mouse embryos in the uterus of autoimmune NZB mice results in developmental neuropathology after birth. Coversely, autoimmune NZB embryos will be transferred to a normal DBA/2 uterine environment in an attempt to prevent the brain anomalies. Appropriate intrastrain control embryo transfers will also be performed. (2) Crossfostering Studies - to assess the role of maternal-derived antibodies (via colostrum and milk) during post natal life on developmental neuropathology, crossfostering experiments will be carried out, and (3) Modulation of Autoimmunity Studies - to determine whether modulation of autoimmune status of the mother alters the expression of neurological lesions. Further, we will investigate whether the development of DBA/2 mice during their fetal life in syngeneic mothers with deliberately induced autoimmunity results in neuropathology. Mice of the above three studies will be subjected to a serological analysis (immunoglobulin isotypes and selected autoantibodies) which will be correlated with the expression of neurological lesions. Selected groups of mice will also be subjected to a battery of behavioral tests. These studies will provide a comprehensive understanding of the relationship of cortical ectopias with immunological parameters and learning disabilities and guide future research on the causes of developmental dyslexia.
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