Dynamic modeling and closed-loop modulation for absence seizures caused by abnormal glutamate uptake from astrocytes

Absence seizures are not only associated with abnormal interactions in basal gangliacorticothalamic (BGCT) circuits, but are also influenced by glial functions. By introducing extracellular glutamate dynamics associated with neurons and astrocytes, we develop a BGCT model containing the astrocytic function module to simulate seizure phenomena resulting from insufficient glutamate uptake from astrocytes. Differential alterations in the occurrence threshold of spike wave discharges (SWDs) are found by comparing the astrocytic function parameter under different GABAA\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\textrm{GABA}_{\textrm{A}}$$\end{document} or GABAB\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\textrm{GABA}_{\textrm{B}}$$\end{document} inhibition degrees from the reticular nuclei (TRN). Specifically, with enhancement from GABAA\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\textrm{GABA}_{\textrm{A}}$$\end{document} inhibition, thresholds undergo the non-monotonic change, whereas raising GABAB\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\textrm{GABA}_{\textrm{B}}$$\end{document} inhibition will always increase thresholds. Afterwards, we reveal the effects of deep brain stimulation (DBS) frequency and timing on seizure waveform under different pathological degree. Most importantly, a closed-loop strategy based on extracellular glutamate concentration is proposed, which is more on-demand and current-saving than traditional open-loop stimulation. Our theoretical study may provide insights into understanding the astrocytic triggers of absence seizures and further designing regulatory strategies.