Exploring the contribution of extracellular vesicles to epileptogenesis in TLE and DS

About This Grant

PROJECT SUMMARY Epilepsy is a common neurological disorder that affects approximately 50 million people worldwide. Approximately 30% of patients with epilepsy have treatment-resistant (refractory) seizures, presenting a major clinical challenge and burden. The acquired and genetic forms of epilepsy represent the two major classes of epilepsy, and these arise mainly from neurological insults and genetic mutations, respectively. Temporal lobe epilepsy (TLE) is the most common form of acquired epilepsy, and mesial temporal lobe epilepsy (MTLE) is the most common subtype of TLE. Dravet syndrome (DS), the most common form of genetic epilepsy, is a catastrophic pediatric disorder which is most frequently caused by mutations in the SCN1A voltage-gated sodium channel. The mechanisms that contribute to the eventual development of seizures and associated comorbidities in MTLE and DS are still incompletely understood, and further research on the cellular and molecular changes that underlie these disorders is necessary in order to facilitate the development of improved treatments. Extracellular vesicles (EVs) are small, membranous particles that are naturally released by cells. EVs play an important role in intercellular communication and have been shown to possess anti-inflammatory and neuroprotective properties. Accordingly, the administration of EVs isolated from healthy, non-pathogenic cellular sources such as mesenchymal stem cells (MSEs) and neural stem cells have been demonstrated to reduce pathology in models of MTLE, stroke, TBI, and neurodegenerative disorders. Our preliminary data also suggests that endogenously-released EVs in the brain (i.e. brain derived EVs or BDEVs) from naïve wild-type mice have anti-inflammatory and cell protective properties. However, in certain disease states, BDEVs can become dysregulated and contribute to neuroinflammation and disease pathology. Little is known about the role of BDEVs (i.e., protective versus pathogenic) during the development of epilepsy. To date, only two studies have examined BDEVs in rodent MTLE models. While both studies identified changes in the expression of BDEV miRNAs following status epilepticus, neither study examined whether the functional properties of the BDEVs were altered. Furthermore, whether BDEVs are altered in genetic epilepsies and contribute to disease development is completely unknown. Hence, the objective of this exploratory R21 proposal is to establish whether BDEV properties are altered in mouse models of MTLE and DS. Importantly, the analysis of two models with distinct epileptogenic mechanisms will establish conserved and epilepsy subtype-specific BDEV contributions. The data generated in this study will provide new information on the role of BDEVs in the development of acquired and genetic forms of epilepsy, and may potentially identify novel targets for therapeutic intervention.