Neuroprotective Role of Gap Junctions in a Neuron Astrocyte Network Model

Abstract

A detailed biophysical model for a neuron/astrocyte network is developed to explore mechanisms responsible for the initiation and propagation of cortical spreading depolarizations and the role of astrocytes in maintaining ion homeostasis, thereby preventing these pathological waves. Simulations of the model illustrate how properties of spreading depolarizations, such as wave speed and duration of depolarization, depend on several factors, including the neuron and astrocyte Na(+)-K(+) ATPase pump strengths. In particular, we consider the neuroprotective role of astrocyte gap junction coupling. The model demonstrates that a syncytium of electrically coupled astrocytes can maintain a physiological membrane potential in the presence of an elevated extracellular K(+) concentration and efficiently distribute the excess K(+) across the syncytium. This provides an effective neuroprotective mechanism for delaying or preventing the initiation of spreading depolarizations.

Neuromodulation of Glial Function During Neurodegeneration

“…Astrocytes are functionally coupled via gap junctions comprised of a pair of connexons which connect across intracellular space (Nagy et al, 2001 ; Johnson et al, 2018 ) and link the cytoplasm of two cells (Hofer and Dermietzel, 1998 ; Wei et al, 2004 ; Wilson and Mongin, 2019 ). Astrocytic gap junctions have several functions, including facilitation of electrical and chemical communication between cells (Kettenmann and Ranson, 1988 ), affecting neuronal rhythmicity in the brainstem (Kadala et al, 2015 ; Condamine et al, 2018 ), distribution of excess K + from high concentration regions to low concentration areas, and allowing transmembrane transport of small molecules to share metabolic demands across cells (Huguet et al, 2016 ). This communication method allows for astrocytes to work as a syncytium and propagate signals through the astrocytic network (Halassa et al, 2007 ).…”

Calcium-Binding Proteins as Determinants of Central Nervous System Neuronal Vulnerability to Disease

“…Similarly, investigation of neuronal survival to blood glutamate in the area postrema found calretinin-expressing neurons to be differentially sensitive depending upon their position, presumably reflecting the variable capillary permeability in different regions of this circumventricular organ [83]. A second difference between the in vivo and in vitro investigations may involve an increased susceptibility of neurons to injury following their removal from their in vivo setting, whereby a loss of endogenous supplies (such as glia-secreted factors) and a disturbance in their network connectivity may result in a loss of neuroprotective support [84,85]. Thus, these types of experiments may not accurately reflect the complexity of the in vivo disease paradigm.…”

GABAergic neurons and NaV1.1 channel hyperactivity: a novel neocortex-specific mechanism of Cortical Spreading Depression

“…We replaced the expression describing its dependence on the intracellular sodium and extracellular potassium concentrations with a more realistic one developed by (Kager et al, 2000), which is based on experimental data, and we introduced a voltage dependence of the pump function as in (Bouret et al, 2014), to prevent the membrane potential from reaching excessively negative values when recovering from a depolarization block. We used the half activation concentration values from (Huguet et al, 2016) and a maximal pump rate of 30 µA cm −2 at −70 mV. We also modified a number of additional minor aspects.…”