Network Dynamics of 4-Aminopyridine-Induced Ictogenesis
- Author(s): Myers, Timothy
- Advisor(s): Bazhenov, Maxim
- et al.
It is well established that one-third of epilepsy patients receive an intractable prognosis, yet 13% of those referred with a pharmacoresistant diagnosis are determined not to have refractory epilepsy. The literature attributes this discrepancy to the misdiagnosis and/or mistreatment of epilepsy syndromes. There is a significant gap in knowledge with respect to the pathogenesis of seizure disorders. Therefore, further insight into the mechanisms of ictogenesis is critical. Here, I present a multimodal series of studies exploring the 4-aminopyridine (4AP) chronic model of epilepsy. The research incorporates computational, experimental, and translational experiments with methods drawing upon the fields of neuropharmacology, electrophysiology, optophysiology and biorealistic modeling. The aims of the research are three-fold: (1) propose a novel mechanism for ictogenesis, (2) elucidate the spatiotemporal dynamics and role of KCC2 in 4AP-induced ictogenesis, and (3) demonstrate proof of concept for the practical application of spectral-domain optical coherence tomography (SD-OCT) in bedside treatment of seizure disorders. Our computational modeling predicts that highly synchronized inhibition, in response to reduction of IA, can drive seizure generation. This mechanism involves the recruitment of the KCC2 cotransporter to compensate for the large increase of intracellular chloride. Upon recruitment of the KCC2 cotransporter, substantial potassium efflux increases extracellular potassium resulting in the net depolarization of excitatory neurons and seizure generation. Furthermore, I demonstrate that spatiotemporal patterns of 4AP epileptiform activity reveal a dose-dependent response with increased waveform complexity at higher concentrations. I show that pharmacological inhibition of KCC2 further reinforced the computational simulations and implicated KCC2 in potassium channelopathy-induced seizure disorders. Lastly, we determine that SD-OCT sensitivity is sufficient to detect a decrease in backscattered light intensity in 4AP perfused hippocampal slices. We developed a protocol to correlate SD-OCT and simultaneous electrophysiological recordings using a 60-channel multielectrode array (MEA). These findings encourage future consideration of SD-OCT in the clinical setting for seizure diagnosis and treatment. Together, these studies address a critical research need in the study of epilepsy and raise additional questions for future research.