Seizure-like afterdischarges simulated in a model neuron

Abstract

To explore non-synaptic mechanisms in paroxysmal discharges, we used a computer model of a simplified hippocampal pyramidal cell, surrounded by interstitial space and a "glial-endothelial" buffer system. Ion channels for Na+, K+, Ca2+ and Cl- ion antiport 3Na/Ca, and "active" ion pumps were represented in the neuron membrane. The glia had "leak" conductances and an ion pump. Fluxes, concentration changes and cell swelling were computed. The neuron was stimulated by injecting current. Afterdischarge (AD) followed stimulation if depolarization due to rising interstitial K+ concentration ([K+]o) activated persistent Na+ current (INa.P). AD was either simple or self-regenerating; either regular (tonic) or burst-type (clonic); and always self-limiting. Self-regenerating AD required sufficient INa.P to ensure re-excitation. Burst firing depended on activation of dendritic Ca2+ currents and Ca-dependent K+ current. Varying glial buffer function influenced [K+]o accumulation and afterdischarge duration. Variations in Na+ and K+ currents influenced the threshold and the duration of AD. The data show that high [K+]o and intrinsic membrane currents can produce the feedback of self-regenerating afterdischarges without synaptic input. The simulated discharge resembles neuron behavior during paroxysmal firing in living brain tissue.

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

“…The morphology of the computer model used here is similar to the one described in Kager et al (2000Kager et al ( , 2002Kager et al ( , 2007 as the "simplified" cell, and it is illustrated in Kager et al (2007).…”

“…The basal dendrite and segments 0, 4 and 5 of the apical dendrite were implemented as passive dendrite segments; the active dendrite segments were apical 1, 2 and 3 (counting from nearest to farthest from the soma; see Fig. 1 in Kager et al 2007). The soma membrane contained the classical fast sodium channel (generating the transient Na + current, I Na,T ) necessary for action potential firing.…”

“…[Ca 2+ ] i controlled the calcium dependent inactivation of I Ca,L , and the activation of a calcium-dependent potassium current I K,SK . All equations that govern these currents have been given in detail in Kager et al (2000Kager et al ( , 2002Kager et al ( , 2007.…”

“…Calcium was not represented in the glial cytosol. The leak potassium conductance was much more dominating than the one of the neuron membrane, yielding a resting membrane potential in the glial cell of −88 mV (for details see Kager et al 2007, Somjen et al 2008.…”

“…Earlier we have simulated seizure-like and SD-like processes (Kager et al 2000(Kager et al , 2002(Kager et al , 2007Somjen et al 2008) in a neuron model based on the NEURON simulation environment of Hines, Moore and Carnevale (Hines and Carnevale 1997). It appeared that SD and HSD could be simulated in the presence of either a persistent Na + current (I Na,P ) or one that resembled NMDA-controlled current (I NMDA ).…”