Effect of co-transporter blockers on non-synaptic epileptiform activity—computational simulation

Abstract

The important role of cation-chloride co-transporters in epilepsy is being supported by an increasing number of investigations. However, enormous complexity is involved since the action of these co-transporters has effects on the ionic homeostasis influencing directly the neuronal excitability and the tissue propensity to sustain seizure. To unravel the complex mechanisms involving the co-transporters action during seizure, this paper shows simulations of non-synaptic epileptiform activity and the effect of the blockage of the two different types of cation-chloride co-transporters present in the brain: Na, K and 2Cl co-transporter (NKCC) and K and Cl co-transporter (KCC). The simulations were performed with an electrochemical model representing the non-synaptic structure of the granule cell layer of the dentate gyrus (DG) of the rat hippocampus. The simulations suggest: (i) the potassium clearance is based on the systemic interplay between the Na/K pump and the NKCC co-transporters; (ii) the simultaneous blockage of the NKCC of the neurons and KCC of glial cells acts efficiently suppressing the epileptiform activities; and (iii) the simulations show that depending on the combined blockage of the co-transporters, the epileptiform activities may be suppressed or enhanced.

Enhanced nonsynaptic epileptiform activity in the dentate gyrus after kainate-induced status epilepticus

“…If NKCC1 expression increases and KCC2 expression decreases or does not change, as shown in our results, the inward flow of chloride exceeds its extrusion, and intracellular chloride accumulation may occur. According to computational simulations (Almeida et al, 2008;Lopes et al, 2013), when chloride accumulation is sufficient to make the chloride Nernst potential exceed the membrane potential, this accumulation constitutes an important mechanism of neuronal depolarization. This is a plausible explanation for the increase in NEA.…”

pH during non-synaptic epileptiform activity—computational simulations

“…Mechanisms responsible for pH changes in the intra and extracellular space were investigated using the previously designed computational model for the non-synaptic epileptiform activity proposed by Almeida et al (2008) and Lopes et al (2013). The investigation was undertaken with sequential inclusion of cell mechanisms related to ionic transportation.…”

“…Our model was based on that proposed by Almeida et al (2008) and Lopes et al (2013), designed to study mechanisms underlying the nonsynaptic epileptiform activity in the granule cell layer of the hippocampal dentate gyrus.…”

“…In the previous versions of the model (Almeida et al 2008, Lopes et al 2013, Na + /H + (NHE) and HCO 3 − /Cl − (HCE) exchangers were only represented as contributing to control the Na + and Cl − homeostasis. In the present study, these were included to represent the effects of exchangers on concentration changes of H + and HCO , 3 − determining pH changes during the NEA.…”

“…In the absence of the synaptic connections, mechanisms involved in neuronal couplings, the electric field effect and extracellular ionic fluctuations are dependent on gap-junctions (Almeida et al 2008, Volman et al 2011, Lopes et al 2013. As already mentioned, the gap-junction effect was estimated by calculating ionic fluxes using the Goldman-Hodgkin-Katz current equation.…”