Role of KCC2-Dependent Potassium Efflux in 4-Aminopyridine-Induced Epileptiform Synchronization

• DOI: 10.1101/171488
• Publication Date: 2017-08-04T05:10:13Z
• Authors: Oscar C Gonzalez; Zahra Shiri; Giri P Krishnan; Timothy L Myers; Sylvian Williams; Massimo Avoli; Maxim Bazhenov
• Keywords: Interneuron; 4-Aminopyridine; Dravet syndrome

A balance between excitation and inhibition is required to maintain stable brain network dynamics. Traditionally, seizure activity believed arise from the breakdown of this delicate in favor with loss inhibition. Surprisingly, recent experimental evidence suggests that conventional view may be untrue, plays a prominent role development epileptiform synchronization. Here, we explored co-transporter KCC2 onset inhibitory network-induced seizures. Our experiments acute mouse slices either sex revealed optogenetic stimulation parvalbumin- or somatostatin-expressing interneurons induced ictal discharges rodent entorhinal cortex during 4-aminopyridine application. These data point proconvulsive GABAA receptor signaling independent input location (i.e., dendritic vs. somatic). Further, developed biophysically realistic model implementing complex dynamics ion concentrations explore mechanisms leading In agreement results, found seizure-like reduced potassium A-current. Model predicted interneuron triggered firing was accompanied by an increase intracellular chloride subsequent KCC2-dependent gradual accumulation extracellular promoting activity. When reduced, no longer able induce events. Overall, our study provides for depends on involvement co-transporter.