Surface charge impact in low-magnesium model of seizure in rat hippocampus

Abstract

Putative mechanisms of induction and maintenance of seizure-like activity (SLA) in the low Mg(2+) model of seizures are: facilitation of NMDA receptors and decreased surface charge screening near voltage-gated channels. We have estimated the role of such screening in the early stages of SLA development at both physiological and room temperatures. External Ca(2+) and Mg(2+) promote a depolarization shift of the sodium channel voltage sensitivity; when examined in hippocampal pyramidal neurons, the effect of Ca(2+) was 1.4 times stronger than of Mg(2+). Removing Mg(2+) from the extracellular solution containing 2 mM Ca(2+) induced recurrent SLA in hippocampal CA1 pyramidal layer in 67% of slices. Reduction of [Ca(2+)](o) to 1 mM resulted in 100% appearance of recurrent SLA or continuous SLA. Both delay before seizure activity and the inter-SLA time were significantly reduced. Characteristics of seizures evoked in low Mg(2+)/1 mM Ca(2+)/3.5 K(+) were similar to those obtained in low Mg(2+)/2 Ca(2+)/5mM K(+), suggesting that reduction of [Ca(2+)](o) to 1 mM is identical to the increase in [K(+)](o) to 5 mM in terms of changes in cellular excitability and seizure threshold. An increase of [Ca(2+)](o) to 3 mM completely abolished SLA generation even in the presence of 5 mM [K(+)](o). A large variation in the ability of [Ca(2+)](o) to stop epileptic discharges in initial stage of SLA was found. Our results indicate that surface charge of the neuronal membrane plays a crucial role in the initiation of low Mg(2+)-induced seizures. Furthermore, our study suggests that Ca(2+) and Mg(2+), through screening of surface charge, have important anti-seizure and antiepileptic properties.

Surface charge impact in nonsynaptic model of epilepsy in rat hippocampus

“…Both cellular depolarization and hyperpolarizing shift of the voltage-gated channel activation cause similar effects on neuronal network activity due to reduced voltage difference between the resting membrane potential and potentials where Na + -channels are activated. Removal of Mg 2+ ions from extracellular solution shifts leftward the half activation and facilitates the amplitude of I Na compared with the 1mmol Mg 2+ solution [12].Our results suggest that the change in the surface charge dramatically affects the probability of induction of low-Ca 2+ SLA, providing evidence that Mg 2+ can reduce cerebral excitability by screening surface charge and support the idea that lack of Mg 2+ could cause epileptic seizures. In previous studies, it was shown that manipulations with surface charge could alter the pattern of epileptiform like activity [19].…”

“…In previous studies, it was shown that manipulations with surface charge could alter the pattern of epileptiform like activity [19]. In previous work we demonstrated that surface charge plays a crucial role in lowMg 2+ model of epilepsy [12].…”

“…Brain was rapidly removed and placed in icecold artificial cerebro-spinal fluid (aCSF). Cerebellum and frontal lobe of the brain were removed and transverse brain slices (500µm) were cut using vibroslicer [12]. The resulting slices were then transferred to the incubation chamber and left to recover for at least one hour before the experiment at room temperature.…”

“…The effect of surface charge on the membrane channel can be assessed by changing extracellular concentrations of cations, which produce a screening effect on surface charge. Decreasing extracellular Ca 2+ or increasing the amount of extracellular negati vely charged polysialic acids results in a significant hyperpolarizing shift of activation of voltagegated Na + -channels [12,13,14]. In the present study, we investigated the effect of various Mg 2+ concentrations in the extracellular solution on the probability to evoke seizure activity, its delay time and pattern of discharges.…”

“…Surface charge on the cellular membrane produced by sialic acid, phosphates, charged lipids, charged amino acids, and other hydrophilic residues of channel proteins creates local electrical fields near the channel voltage sensor [12]. The effect of surface charge on the membrane channel can be assessed by changing extracellular concentrations of cations, which produce a screening effect on surface charge.…”