Anti-epileptic drug resistance is a major obstacle to the clinical management of seizure disorders and affects one third of patients with epilepsy. In addition, patients with genetic generalized epilepsy do not have the option of epilepsy surgery. The focus of this project is to explore the cellular and network basis of anti-epileptic drug response in genetic generalized epilepsy. The candidate has a strong clinical background in epilepsy and has developed significant preliminary work which forms the basis for the proposed research. The central hypothesis of this proposal is that interictal relative gamma power (30-100 Hz) may predict anti-epileptic drug response in absence epilepsy and severe myoclonic epilepsy of infancy (Dravet Syndrome) due to the effect of these drugs on fast-spiking interneurons. The stargazer and tottering mouse models of epilepsy, as well as the Scn1a heterozygous knock-in model of Dravet Syndrome, are ideal for studying this hypothesis since they have mutations which have been associated with fast-spiking interneuron deficits, and these interneurons are critical for the generation of neocortical gamma rhythms. In addition, these models are known to have paradoxical seizure exacerbation with certain anti-epileptic drugs. In this project, using in vivo 2-photon microscopy and simultaneous EEG, post-hoc immunohistochemistry, and in vivo video-EEG monitoring sampling at 2 kHz, the specific aims of this project are to: (1) Determine the neocortical cell-specific and local network responses to anti-epileptic drugs in vivo in 3 models of genetic generalized epilepsy, and (2) Evaluate the effect of anti-epileptic drugs on interictal EEG power between 2-300 Hz in vivo in the same 3 models of genetic generalized epilepsy. This proposal merges the techniques of computational analysis of EEG previously acquired under the mentorship of Sydney Cash, MD, PhD and more recent techniques acquired under the ongoing mentorship of Jeffrey Noebels, MD, PhD (primary mentor), who provides expertise in neurogenesis, and Stelios Smirnakis, MD, PhD (co-mentor), who provides expertise in 2-photon imaging. In the short term, the candidate has assembled a gap-based plan for rigorous training and coursework focusing on developing expertise in 2-photon imaging and patch-clamp techniques in vivo, statistical modelling and analysis, and translational research methodology, while also learning about and treating patients with epilepsy in a clinical context. In the long term, with a strong institutional commitment and abundant resources available in the Texas Medical Center, this training will aid in the candidate's development as an independent clinician- scientist with a unique focus on diminishing pharmacoresistance in patients with epilepsy. Ultimately, the completion of this research will shed new light on the mechanisms of genetic generalized epilepsy and can directly lead to improved drug development and patient care.
Anti-epileptic drugs are ineffective in about one third of patients with epilepsy. The work in this proposal investigates whether the response to anti-epileptic drugs in 3 mouse models of genetic epilepsy may be due to the action of these drugs on specific inhibitory neurons and networks. Completion of this research has the potential to significantly improve drug development and patient care.
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