snx-482 and Status-Epilepticus

A single episode of status epilepticus (SE) induced in rodents by the convulsant pilocarpine, produces, after a latent period of > or = 2 weeks, a chronic epileptic condition. During the latent period of epileptogenesis, most CA1 pyramidal cells that normally fire in a regular pattern, acquire low-threshold bursting behaviour, generating high-frequency clusters of 3-5 spikes as their minimal response to depolarizing stimuli. Recruitment of a Ni(2+)- and amiloride-sensitive T-type Ca(2+) current (I(CaT)), shown to be up-regulated after SE, plays a critical role in burst generation in most cases. Several lines of evidence suggest that I(CaT) driving bursting is located in the apical dendrites. Thus, bursting was suppressed by focally applying Ni(2+) to the apical dendrites, but not to the soma. It was also suppressed by applying either tetrodotoxin or the K(V)7/M-type K(+) channel agonist retigabine to the apical dendrites. Severing the distal apical dendrites approximately 150 microm from the pyramidal layer also abolished this activity. Intradendritic recordings indicated that evoked bursts are associated with local Ni(2+)-sensitive slow spikes. Blocking persistent Na(+) current did not modify bursting in most cases. We conclude that SE-induced increase in I(CaT) density in the apical dendrites facilitates their depolarization by the backpropagating somatic spike. The I(CaT)-driven dendritic depolarization, in turn, spreads towards the soma, initiating another backpropagating spike, and so forth, thereby creating a spike burst. The early appearance and predominance of I(CaT)-driven low-threshold bursting in CA1 pyramidal cells that experienced SE most probably contribute to the emergence of abnormal network discharges and may also play a role in the circuitry reorganization associated with epileptogenesis.

Topics: Amiloride; Animals; Calcium; Calcium Channels, R-Type; Calcium Channels, T-Type; Carbamates; Dendrites; Male; Nickel; Phenylenediamines; Phorbol 12,13-Dibutyrate; Pyramidal Cells; Rats; Recruitment, Neurophysiological; Riluzole; Sodium; Spider Venoms; Status Epilepticus; Tetrodotoxin