Effects of astrocytic mechanisms on neuronal hyperexcitability

While originally astrocytes have been thought to only act as support to neurons, recent studies have implicated them in multiple active roles, including the ability to moderate or alter neuronal firing patterns and to possibly be involved in both the prevention and propagation of epileptic seizures. In this study we propose a new model to incorporate pyramidal cells and interneurons (a common neural circuit in CA3 hippocampal slices) as well as a model of astrocyte. As both potassium and calcium ions have been shown to potentially affect neuronal hyperexcitability, the astrocytic model has both mechanisms--the clearance of potassium through potassium channels (such as KIR, KDR and sodium-potassium pump), and the influence of astrocyte in the synapse (forming the tripartite synapse with calcium-glutamate interactions). Preliminary findings of the model results show that when potassium conductances in the astrocyte are decreased, it results in the accumulation of extracellular potassium, leading to both spontaneous discharges and depolarization block, while the alteration of normal calcium response in the astrocyte can lead to just hyperexcitable conditions without the depolarization block.

section_content: Epileptic seizures affect one in hundred people and about 30% of all patients don't benefit from medication and have to rely on other intervention methods. Current computer models of epilepsy frequently focus on neurons and their interactions to explain both the normal and pathological events in the brain. Recent research has linked glial cell to various cellular processes that are necessary for signal generation and propagation [1]. 

Several mechanisms by which glial cells could influence the rest of the network have been proposed. One mechanism is the effect of potassium clearance on maintaining homeostatic ion concentration in the extracellular matrix which, when impaired, could lead to seizure-like activity [2]. In addition to directly affecting potassium concentration in the extracellular space (ECS), impaired astrocytes become unable to maintain acceptable intracellular chloride concentrations in the neurons, which can cause or extend seizure-like events [3]. 

We introduce a computational model of CA3 region of hippocampus, consisting of a network of an astrocyte and a pyramidal cell with a feedback inhibited interneuron, to investigate the effects of a) potassium clearance and buffering by glial cells, and b) calcium propagation on neuronal hyperexcitability. Each cell was represented using modified Traub's compartment models [4]. Glial contribution was split into two separate factors -K + clearance and buffering, partially revised from Oyehaug [5] and calcium interactions. 

We observe that when potassium clearing mechanisms are present (including inwardly rectifying potassium channel as well as phenomenologically represented spatial buffering), neuronal spiking occurs at normal rates (Figure 1A ). However when these mechanisms are compromised, potassium accumulation occurs and seizure-like spike trains appear. Preliminary model findings point to both (a) the existence of depolarization block within model parameter searches and (b) the significant influence of glial calcium signaling on spontaneous neuronal discharges.

section_name: Acknowledgements

section_content: We would like to acknowledge Canadian Institutes for Health Research (CIHR) for providing the opportunity to investigate neuron-glia interactions under hyperexcitable conditions. 

Published: 21 July 2014
section_name: Acknowledgements