Abstract
Experimental recordings in hippocampal slices indicate that astrocytic dysfunction may cause neuronal hyper-excitation or seizures. Considering that astrocytes play important roles in mediating local uptake and spatial buffering of K+ in the extracellular space of the cortical circuit, we constructed a novel model of an astrocyte-neuron network module consisting of a single compartment neuron and 4 surrounding connected astrocytes and including extracellular potassium dynamics. Next, we developed a new model function for the astrocyte gap junctions, connecting two astrocyte-neuron network modules. The function form and parameters of the gap junction were based on nonlinear regression fitting of a set of experimental data published in previous studies. Moreover, we have created numerical simulations using the above single astrocyte-neuron network module and the coupled astrocyte-neuron network modules. Our model validates previous experimental observations that both Kir4.1 channels and gap junctions play important roles in regulating the concentration of extracellular potassium. In addition, we also observe that changes in Kir4.1 channel conductance and gap junction strength induce spontaneous epileptic activity in the absence of external stimuli.
Highlights
Temporal lobe epilepsy, which has a specific clinical presentation of seizures arising from the hippocampus [1], is a serious health risk to affected individuals
Numerous biological studies have shown that astrocytic Kir4.1 channels and gap junctions between astrocytes act as major K+ clearance mechanisms
These questions were addressed in the present study by constructing novel single astrocyte-neuron network models and a coupled astrocyte-neuron module network connected by an astrocyte gap junction based on existing experimental
Summary
Temporal lobe epilepsy, which has a specific clinical presentation of seizures arising from the hippocampus [1], is a serious health risk to affected individuals. Experimental data suggest that Kir4.1 channels play a prominent role in local uptake of extracellular K+ [8,13,14], and many experimental studies have observed that dysfunction of local uptake by astrocytes or inactivation of astrocytic gap junction protein expression cause the generation or spread of seizure activity [15,16,17,18,19,20]. We investigated the dynamic mechanisms by which dysfunction of K+ uptake or gap junctions leads to changes in extracellular K+ concentration and resultant pathological epileptic discharges using a theoretical study with a computational astrocytic-neural network model
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