Exploring the role of hippocampal hypervascularization in Rett syndrome pathogenesis

Baylor College Of Medicine, Houston TX

Investigators

Abstract

Rett syndrome is a severe neurological disorder caused by mutations in the MECP2 gene, affecting approximately 1 in 10,000 female births. About 70% of individuals with Rett syndrome experience epileptic seizures and nearly one-third of these cases are resistant to treatment, posing a substantial burden for patients. In my recent experiments, I observed an increase in both vascular density and branching within the hippocampus of Rett mice, as compared to wildtype controls. In mouse models of temporal lobe epilepsy, similar vascular changes are driven by vascular endothelial growth factor (VEGF) and contribute to epileptogenesis. Such phenotypes also correlate with the severity of disease in human temporal lobe epilepsy. However, given the broad transcriptomic consequences of MeCP2 dysfunction, it’s not clear whether hippocampal vascular abnormalities in Rett syndrome share the molecular origin or pathological consequences found in other disease models. Through this proposal, I will test the hypotheses that VEGF signaling drives the aberrant vascularization observed in the hippocampus of Rett mice, and that these vascular changes contribute to the development of epilepsy in this model system. This will be accomplished through the following specific aims: VEGF Signaling and Vascular Growth: I will evaluate whether increased VEGF expression in the hippocampus of Rett mice promotes angiogenesis through the activation of VEGFR2. I will measure the differential expression of VEGF and VEGFR2 in both Rett and wild-type tissues using histological methods and quantitative protein analysis. I will target VEGF and VEGFR2 with shRNA-mediated knockdowns to causatively determine the impact of VEGF signaling on vascular anomalies observed in Rett mice. Functional Implications of Angiogenesis in Epileptogenesis: I will employ longitudinal 2-photon imaging coupled with multi-channel EEG to determine the impact of increased vascularization in epileptogenesis in Rett mice. I will chronically inhibit angiogenesis or epileptic activity using pharmacological methods to reveal the relationship between these two phenomena. Through the proposed molecular, electrophysiological, and imaging studies, this project will establish the origins of aberrant hippocampal angiogenesis in Rett syndrome and determine if this phenotype contributes to Rett-associated epilepsy. It will thus provide fundamental insights into the progression of epileptic disease in Rett syndrome and potentially help to identify generalizable targets to treat or delay epileptogenesis for Rett and other disorders.