A dynamics model of neuron-astrocyte network accounting for febrile seizures

Abstract

Febrile seizure (FS) is a full-body convulsion caused by a high body temperature that affect young kids, however, how these most common of human seizures are generated by fever has not been known. One common observation is that cortical neurons become overexcited with abnormal running of sodium and potassium ions cross membrane in raised body temperature condition, Considering that astrocyte Kir4.1 channel play a critical role in maintaining extracellular homeostasis of ionic concentrations and electrochemical potentials of neurons by fast depletion of extracellular potassium ions, we examined here the potential role of temperature-dependent Kir4.1 channel in astrocytes in causing FS. We first built up a temperature-dependent computational model of the Kir4.1 channel in astrocytes and validated with experiments. We have then built up a neuron-astrocyte network and examine the role of the Kir4.1 channel in modulating neuronal firing dynamics as temperature increase. The numerical experiment demonstrated that the Kir4.1 channel function optimally in the body temperature around 37 °C in cleaning 'excessive' extracellular potassium ions during neuronal firing process, however, higher temperature deteriorates its cleaning function, while lower temperature slows down its cleaning efficiency. With the increase of temperature, neurons go through different stages of spiking dynamics from spontaneous slow oscillations, to tonic spiking, fast bursting oscillations, and eventually epileptic bursting. Thus, our study may provide a potential new mechanism that febrile seizures may be happened due to temperature-dependent functional disorders of Kir4.1 channel in astrocytes.

Supplementary information: The online version contains supplementary material available at 10.1007/s11571-021-09706-w.

Keywords: Febrile seizures; Hyperthermia; Kir4.1 channel.

Fig. 1

a. Sketches of the computational model. b. The steady-state opening of the gates m along with v_A and [K⁺]_o in our model. (c, d and e). Superimposition of astrocytic Kir4.1 channel current (I_Kir4.1), extracellular potassium concentration ([K⁺]_o), and astrocytic membrane potential ([K⁺]_A) time series obtained from the Kir4.1 model in Ref. (Sibille et al. 2015) (black line, g_kir = 380 ps) and our model (red line, g_kir = 60 ps) generated by a single pulse simulation f(t) = δ(t), respectively. (f, h and i). Quantification of astrocytic Kir4.1 channel current, extracellular potassium concentration, and astrocytic membrane potential kinetics extracted from numerical simulations using the Kir4.1 model in Ref. (Sibille et al. 2015) (black) and the presented model (red)

Fig. 2

a. Adapted experimental data of the K⁺ concentration in the extracellular space ([K⁺]_o) and astrocyte ([K⁺]_A) in Kir4.1 channel control and blocked states during and after a 10 s stimulus, interpolated from Fig. 7 in Ballanyi et al. (Ballanyi et al. 1987). b The simulation results of [K⁺]_o and [K⁺]_A corresponding to the experimental results using our model

Fig. 3

Spontaneous neuronal firing patterns as a function of temperature in the absence of external stimulus input. Time trains of the neural membrane potential V (mV) (black lines), astrocyte membrane potential V_A (mV) (red lines) and extracellular K⁺ concentration ([K⁺]_o) at temperatures (a), 37 °C (b), 38.0 °C (c) and 40 °C (d), respectively, found from the model equations presented in the model section. E and F. Neuron firing frequencies in the total 80 s and every periodic firing period as temperature increases. H. The action potential demonstrates a large and prolonged afterhyperpolarization (AHP) for low temperature (e.g., T = 22 °C and 37 °C, respectively) and a smaller and shorter duration AHP for higher temperatures (e.g., T = 38 and 40 °C, respectively)

Fig.4

Neuron action potential and the corresponding Na⁺ and K⁺ currents of neuron, Kir4.1 channel current and [K⁺]_o during action potential generation for temperature at 22 °C (a), 37 °C (b), and 38 °C (c), 40 °C (d), respectively. Note that the overlap of Na⁺ and K⁺ currents during action potential generation is also reduced when temperature increases. The action potential demonstrates a large and prolonged afterhyperpolarization (AHP) for low temperature (e.g., T = 22 °C and 37 °C, respectively) and a smaller and shorter duration AHP for higher temperatures (e.g., T = 38 and 40 °C, respectively)

Fig. 5

Neuron action potential and the corresponding Na⁺ and K⁺ currents of neuron, Kir4.1 channel current and [K⁺]_o during action potential generation for temperature at 40 °C during different period