Mechanisms and modulation of nonsynaptic epileptiform activity.

摘要

Non-synaptic interactions between cells in the CNS have been eclipsed by our increasingly detailed understanding of chemical synapses, however, they play a significant role in modulating both normal and pathological brain function. In particular, non-synaptic mechanisms (electronic and ephaptic interaction, intracellular and extracellular ionic transients, osmolarity, pH, etc.) play a critical role in epileptic seizure threshold. Thus, modulation of these mechanisms represents a powerful approach to controlling seizures. Furthermore, “non-synaptic” epileptiform activity, which does not require synaptic function for event initiation, propagation, and termination, has been demonstrated in-vitro. Therefore, we investigated those mechanisms contributing to non-synaptic epileptogenesis and the feasibility of controlling seizures by modulating these mechanisms.; The role of different non-synaptic interactions in modulating non-synaptic burst frequency, amplitude, and duration was determined to examine factors contributing to non-synaptic burst initiation, size, and termination, and the potential of developing anti-convulsants targeting each of these factors. Antagonists of neuronal excitability, gap junctions, and potassium channels modulated burst frequency, amplitude, and duration differently and could also suppress spontaneous bursting.; Those conditions sufficient for generating non-synaptic activity were studied to further characterize the mechanisms of non-synaptic epileptogenesis and the potential of such genesis in-vivo. Cd+2, a Ca+2 channel antagonist, and Veratridine, a sodium channel enhancer, in the presence of increased neuronal excitability and normal (2 mM) Ca+2 levels, induced spontaneous non-synaptic epileptiform activity. These results showed that a reduction in extracellular Ca +2 is not required for non-synaptic bursting and that specific channel defects could potentially lead to non-synaptic bursting in-vivo.; High frequency electric fields suppress epileptiform activity in-vitro via a non-synaptic mechanism. This mechanism was found to be neuronal depolarization block induced by extracellular potassium buildup, and may explain the anti-convulsant effects of clinical high frequency deep brain stimulation (DBS).; Together, the results of these studies, provide powerful insight into the mechanisms of non-synaptic epileptogenesis and DBS, and emphasize the need to further explore the synaptic dependence of seizures in-vivo as well as the feasibility of controlling seizures with non-synaptic treatments.