Potassium-mediated positive feedback in astroglia-neuron interaction

Model Status

This CellML model is a tranlsation based on the orignal paper and Matlab code. The model runs in both COR and OpenCell to recreate the published results. This particular version of the model recreates Figure 2B, with a stimulus duration of 0.4s.

Model Structure

ABSTRACT: The chain of events where a neural activity-induced elevation of the extracellular space (ECS) potassium concentration ([K+]o) is followed by a decreased neuronal firing threshold which in turn causes increased neural activity, represents a positive feedback loop. Here we combine a relatively detailed model of glial membrane transport of water and ions and a Hodgkin-Huxley type neuron model to examine the effectof perturbing the magnitudes of transport rates in the glial membrane that may influence this feedback. The perturbations reflect pathological conditions and/or heterogeneity in glial membrane transporter density. When exposed to elevated [K+]o, the combined model responds either (i) by a brief period of neuronal firing followed by a rapid drop in [K+]o or (ii) by a much longer period where the neuron experiences depolarization block during which [K+]o first increases and later slowly returns to baseline levels. By solving the model equations repeatedly for a large number of empirically valid parameter sets, we find that both the high [K+]o-induced duration of neuronal firing and the prevalence of depolarization block show high sensitivities to variation in the time scale of the glial membrane dynamics and to the magnitudes of the sodium-potassium pump rate and the potassium ion channel conductance. In contrast, firing duration is much less sensitive to perturbations of the magnitude of Na+/K+/2Cl- (NKCC1) cotransporter permeability and Na+/2HCO-3 (NBC) cotransporter conductance. An analysis focusing on the model's ability to fire spontaneously discloses the feedback mechanism and allows us to predict which combinations of ion concentrations that give rise to spontaneous firing of action potentials. The results suggest that when [K+]o becomes elevated, spatiotemporal heterogenity of ion and water transport across the astroglialmembrane in the brainmay cause very different potassium clearance profiles that are possibly of biomedical importance. The above insights point to the importance of combining neuronal and astroglial models of some sophistication in order to disclose phenomena associated with the astroglia-neuron interaction.

Schematic diagram of the model displaying the channels, pumps and exchangers allowing ion transfer between the neuron, the extracellular matrix and the glia.