Upregulation of a T-Type Ca²⁺Channel Causes a Long-Lasting Modification of Neuronal Firing Mode after Status Epilepticus

Abstract

A single episode of status epilepticus (SE) causes numerous structural and functional changes in the brain that can lead to the development of a chronic epileptic condition. Most studies of this plasticity have focused on changes in excitatory and inhibitory synaptic properties. However, the intrinsic firing properties that shape the output of the neuron to a given synaptic input may also be persistently affected by SE. Thus, 54% of CA1 pyramidal cells, which normally fire in a regular mode, are persistently converted to a bursting mode after an episode of SE induced by the convulsant pilocarpine. In this model, intrinsic bursts evoked by threshold-straddling depolarizations, and their underlying spike afterdepolarizations (ADPs), were resistant to antagonists of N-, P/Q-, or L-type Ca2+ channels but were readily suppressed by low (30-100 microm) concentrations of Ni2+ known to block T- and R-type Ca2+ channels. The density of T-type Ca2+ currents, but not of other pharmacologically isolated Ca2+ current types, was upregulated in CA1 pyramidal neurons after SE. The augmented T-type currents were sensitive to Ni2+ in the same concentration range that blocked the novel intrinsic bursting in these neurons (IC50 = 27 microm). These data suggest that SE may persistently convert regular firing cells to intrinsic bursters by selectively increasing the density of a Ni2+-sensitive T-type Ca2+ current. This nonsynaptic plasticity considerably amplifies the output of CA1 pyramidal neurons to synaptic inputs and most probably contributes to the development and expression of an epileptic condition after SE.

ACTH Induces Cav3.2 Current and mRNA by cAMP-dependent and cAMP-independent Mechanisms

“…Overexpression of this specific T-type Ca 2ϩ channel in neurons has been shown to play a significant role in various forms of epilepsy, as well as neuropathic pain (51)(52)(53). To understand the molecular basis of the pathophysiology of diseases such as these, it will be essential to identify the signaling mechanisms that regulate Ca v 3.2 expression.…”

Massive and Specific Dysregulation of Direct Cortical Input to the Hippocampus in Temporal Lobe Epilepsy

“…Feedforward inhibition may also be compromised by loss of interneurons (Houser and Esclapez, 1996;Dinocourt et al, 2005). It is also possible that intrinsic, regenerative boosting effects on temporoammonic EPSPs mediated by upregulation of T-type Ca 2ϩ conductance and downregulation of A-type potassium and hyperpolarization-activated H-type cationic conductances in CA1 pyramidal cell dendrites may contribute to enhanced efficacy in this pathway (Su et al, 2002;Shah et al, 2004;Bernard et al, 2004).…”

KV7/M Channels Mediate Osmotic Modulation of Intrinsic Neuronal Excitability

“…3Cd). At a lower concentration of Ni 2ϩ (100 M) that preferentially blocks T-type and R-type Ca 2ϩ currents (Lee et al, 1999;Williams et al, 1999) and suppresses T-type Ca 2ϩ current-driven bursting (Su et al, 2002;Yaari et al, 2007), Ni 2ϩ only slightly enhanced hyposmotic bursting ( Fig. 3Dab) (n ϭ 2).…”

“…Direct potentiation of these potentials by Ca 2ϩ currents was found during postnatal development (Magee and Carruth, 1999;Chen et al, 2005;Metz et al, 2005), during epileptogenesis (Sanabria et al, 2001;Su et al, 2002;Yaari et al, 2007), and after pharmacological blockage of A-type K ϩ current in the apical dendrites (Magee and Carruth, 1999). To identify the inward currents driving hyposmotic bursting, we tested its sensitivity to Na ϩ and Ca 2ϩ channel blockers.…”