Calcium sensitive non-selective cation current promotes seizure-like discharges and spreading depression in a model neuron

Abstract

As described by others, an extracellular calciumsensitive non-selective cation channel ([Ca 2+ ] o -sensitive NSCC) of central neurons opens when extracellular calcium level decreases. An other non-selective current is activated by rising intracellular calcium ([Ca 2+ ] i ). The [Ca 2+ ] osensitive NSCC is not dependent on voltage and while it is permeable by monovalent cations, it is blocked by divalent cations. We tested the hypothesis that activation of this channel can promote seizures and spreading depression (SD). We used a computer model of a neuron surrounded by interstitial space and enveloped in a glia-endothelial "buffer" system. Na + , K + , Ca 2+ and Cl − concentrations, ion fluxes and osmotically driven volume changes were computed. Conventional ion channels and the NSCC were incorporated in the neuron membrane. Activation of NSCC conductance caused the appearance of paroxysmal afterdischarges (ADs) at parameter settings that did not produce AD in the absence of NSCC. The duration of the AD depended on the amplitude of the NSCC. Similarly, NSCC also enabled the generation of SD. We conclude that NSCC can contribute to the generation of epileptiform events and to spreading depression. (Caeser et al. 1993;Crepel et al. 1994) and substantia nigra inhibitory neurons (Lee and Tepper 2007). The TRPM4b channel, which is expressed in mammalian neurons, has been characterized as a [Ca 2+ ] i -activated, Ca 2+ -impermeable, monovalent cation-permeable channel (Fleig and Penner 2004;Launay et al. 2002). Since uptake of Ca 2+ into neurons results simultaneously in an increase in [Ca 2+ ] i and a decrease in [Ca 2+ ] o , if the two Ca 2+ sensitive currents co-exist in the same cell, they are expected to reinforce one another and in fact could perhaps be generated by the same channel (see Section 3).

What Is the Clinical Relevance of In Vitro Epileptiform Activity?

“…An exception was area CA1 in rat and mouse hippocampus, where the packing density of neurons is higher, promoting ephaptic interactions that are thought to be enhanced by lowered extracellular calcium. On the other hand, cation channels [ 37 ] and more recently certain TRP channels are activated by decreasing either Ca or Mg concentration [ 91 ]; this is not only important for spreading depolarization [ 80 ] but possibly also for generation of seizures and cell death [ 62 ]. The regulation of these excitatory channels by Ca and the activitydependent decrease in extracellular Ca suggests a new mechanism for seizure spread and for modifying seizure generalization.…”

Computer simulations of neuron-glia interactions mediated by ion flux

“…Besides K + , changes in the distribution of Ca 2+ also influenced the neuron responses and these effects are also presented. In a companion paper we explore the potential role of calcium-sensing non-specific cation current in facilitating seizures and SD (Somjen et al 2008).…”

TRPC3 mediates hyperexcitability and epileptiform activity in immature cortex and experimental cortical dysplasia

“…These results suggest that anti-TRPC3 antibody and Pyr3 completely block TRPC3 channels and that low Ca/low Mg-induced depolarization in dysplastic cortex is primarily mediated by TRPC3 channels. The small, residual depolarization after TRPC3 channels are blocked may be mediated by other channels such as other nonselective cation ion channels or L-type Ca 2ϩ channels (Pohl et al 1992;Somjen et al 2009). …”

“…Other studies have demonstrated that low Ca can excite hippocampal pyramidal neurons through activation of novel and unidentified nonselective cation channels that are not blocked by specific inhibitors of known voltage-gated or ligand-gated ion channels (Chu et al 2003;Xiong et al 1997;Xiong and MacDonald 1999). A computer modeling study showed that activation of nonselective cation channels in low Ca is sufficient to generate epileptiform activity (Somjen et al 2009). Another study in cultured pyramidal neurons revealed that activation of those channels could induce depolarization in low Ca and low Mg, suggesting that those channels could constitute a major component of enhanced neuronal excitability during epileptic seizures (Xiong et al 2001).…”

“…Ca and Mg at 1ϳ2 mM is often used in in vitro slice electrophysiological experiments. Previous studies have demonstrated that when Ca and Mg levels are within normal ranges, the activities of unidentified nonselective cation channels are greatly inhibited (Somjen et al 2009;Xiong et al 1997), and only a relatively small tonic current is permitted to flow through them to add to the resting conductance of the cell (Somjen et al 2009). Those channels are activated to different extents when Ca and/or Mg are low (Albert et al 2006;Thorneloe and Nelson 2004;Xiong et al 1997Xiong et al , 2001Zhou et al 2008) and are maximally activated when both are maximally low, e.g., 0 mM (Xiong et al 1997).…”