Astrocytic Kir4.1 channels and gap junctions account for spontaneous epileptic seizure

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.

Downregulation of Astrocytic Kir4.1 Potassium Channels Is Associated with Hippocampal Neuronal Hyperexcitability in Type 2 Diabetic Mice

“…In addition, it has been shown that downregulation of Kir4.1 channels affects overall ion gradients and also impairs glutamate uptake by astrocytes [12,13]. There are numerous theoretical analyses supporting the spatial relationship between passive and active modulation of [K + ] o by astrocytes and the initiation or maintenance of epileptiform activity [54][55][56]. Furthermore, cell depolarization and impaired ion gradients inhibit glutamate transporter function and cause transporter reversal, thus glutamate release from the cell, which could further affect neuronal excitability [57,58].…”

Synapses and neural communication in neuropathological conditions

“…Furthermore, GJs in astrocytes play a crucial role in ionic regulation; particularly, they can change the concentration of potassium ions. Changes in the strength of GJ coupling can cause neuronal hyperexcitability, and consequently, spontaneous epileptic activity 26 , which ultimately leads to astrocyte uncoupling. Finally, there is evidence that pannexin 1 (Panx1) contributes to the maintenance of epileptic seizures by releasing ATP.…”

Optogenetic manipulation of astrocytes from synapses to neuronal networks: A potential therapeutic strategy for neurodegenerative diseases

“…There is a class of channels that are also specifically expressed on astrocytes: inwardly rectifying potassium channel 4.1 (Kir4.1) (Bataveljic et al, 2012). They play a key role in homeostasis by either net uptake of potassium or by potassium spatial buffering function, loss of which results in seizure susceptibility and epileptogenesis (Du, Li, Chen, Yu, & Wu, 2018;Hinterkeuser et al, 2000;Schröder et al, 2000;Sicca et al, 2016). Striatum astrocytes from HD mouse model have a reduced buffering capacity for extracellular potassium, which may be caused by down-regulation of Kir4.1 and lead to disturbance of glutamate homeostasis, thus resulting in excitotoxic neurodegeneration (Khakh & Sofroniew, 2014).…”