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A single episode of status epilepticus (SE) induced in rodents by the convulsant pilocarpine, produces, after a latent period of ≥ 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 Ni2+- and amiloride-sensitive T-type Ca2+ current (ICaT), shown to be up-regulated after SE, plays a critical role in burst generation in most cases. Several lines of evidence suggest that ICaT driving bursting is located in the apical dendrites. Thus, bursting was suppressed by focally applying Ni2+ to the apical dendrites, but not to the soma. It was also suppressed by applying either tetrodotoxin or the KV7/M-type K+ channel agonist retigabine to the apical dendrites. Severing the distal apical dendrites ∼150 μm from the pyramidal layer also abolished this activity. Intradendritic recordings indicated that evoked bursts are associated with local Ni2+-sensitive slow spikes. Blocking persistent Na+ current did not modify bursting in most cases. We conclude that SE-induced increase in ICaT density in the apical dendrites facilitates their depolarization by the backpropagating somatic spike. The ICaT-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 ICaT-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.
A variety of brain insults can induce the manifestation of temporal lobe epilepsy, the most common human epileptic syndrome (Engel et al. 1997). The processes underlying temporal lobe epileptogenesis have been studied most extensively in models of status epilepticus (SE) (Morimoto et al. 2004). In these animal models, a single episode of SE evoked by chemical or electrical stimulation of mesial temporal lobe structures, causes, after a latent period of several weeks, the emergence of spontaneous seizures. Once these appear, they are sustained for the rest of the animal's life. During the latent period of epileptogenesis, the animals appear behaviourally normal, though electroencephalographic (EEG) recordings disclose the appearance of interictal ‘spikes’ (Stewart & Leung, 2003). Numerous long-lasting changes in excitatory and inhibitory synaptic functions have been associated with epileptogenesis following SE (Dudek et al. 2002; Morimoto et al. 2004). In addition, intrinsic neuronal properties are also persistently altered by SE. Thus, SE induced by the convulsant pilocarpine (pilocarpine-SE) causes a dramatic and enduring increase in the propensity of CA1 (Sanabria et al. 2001), subicular (Wellmer et al. 2002) and layer V neocortical pyramidal neurons (Sanabria et al. 2002) to fire in burst mode. In CA1 cells, where this plasticity phenomenon was first discovered, many regular-firing pyramidal cells convert to a low-threshold bursting mode, generating high-frequency clusters of 3–5 spikes as their minimal response to depolarizing stimuli or even spontaneously (Sanabria et al. 2001). The spontaneous bursters, which comprise ∼10% of the total neuronal population, serve as the initiators and pacemakers of spontaneous epileptiform bursts, during which the entire CA1 network is engaged in repetitive discharge (Sanabria et al. 2001).
Which ionic mechanisms underlie intrinsic bursting in pyramidal neurons that experienced SE (SE-experienced)? A somatic burst is generated when the spike afterdepolarization (ADP) is sufficiently large to attain spike threshold and trigger a second spike, which is also followed by a large ADP, and so forth (Jensen et al. 1996). In ordinary adult CA1 pyramidal cells, the spike ADP and associated bursting are driven predominantly by persistent Na+ current (INaP), as evidenced by their sensitivity to blockers of this current and refractoriness to blockers of Ca2+ currents (Azouz et al. 1996; Su et al. 2001; Yue et al. 2005). Yet, intrinsic bursting in most SE-experienced neurons was readily suppressed by low concentrations (50–100 μm) of Ni2+, implicating a Ni2+-sensitive Ca2+ current in its generation (Sanabria et al. 2001; Su et al. 2002). In agreement with this, we have shown a marked and selective up-regulation of the low-voltage-activated (T-type) Ca2+ current (ICaT) in SE-experienced neurons (Su et al. 2002), assigning ICaT a critical role in bursting. However, the possible contribution of INaP to this discharge mode was not explored.
Here we combined several experimental approaches to further elucidate the ionic mechanisms underlying the de novo intrinsic bursting in SE-experienced CA1 pyramidal cells. Three issues were examined regarding this aberrant activity: (i) the contribution of ICaTversus that of the high-voltage-activated R-type Ca2+ current (ICaR); (ii) the subcellular localization of the underlying ICaT; and (iii) the contribution of INaP. Our data show conclusively that bursts arise via activation of ICaT in the apical dendrites by backpropagating somatic spikes. Whereas a secondary contribution of ICaR to bursting cannot be excluded, activation of INaP does not play a role in this activity in most cases.