Dynamical modeling and analysis of epileptic discharges transition caused by glutamate release with metabolism...

Glutamate (Glu) is a crucial excitatory neurotransmitter in the central nervous system that transmits brain information by activating excitatory receptors on neuronal membranes. Physiological studies have demonstrated that abnormal Glu metabolism in astrocytes is closely related to the pathogenesis of epilepsy. The astrocyte metabolism processes mainly involve the Glu uptake through astrocyte EAAT2, the Glu-glutamine (Gln) conversion, and the Glu release. However, the relationship between these Glu metabolism processes and epileptic discharges remains unclear. In this paper, we propose a novel neuron-astrocyte model by integrating the dynamical modeling of astrocyte Glu metabolism processes, which include Glu metabolism in astrocytes consisting of the Glu uptake, Glu-Gln conversion, Glu diffusion, and the resulting Glu release as well as Glu-mediated bidirectional communication between neuron and astrocyte. Furthermore, the influences of astrocyte multiple Glu metabolism processes on the Glu release and dynamics transition of neuronal epileptic discharges are verified through numerical experiments and dynamical analyses from various nonlinear dynamics perspectives, such as time series, phase plane trajectories, interspike intervals, and bifurcation diagrams. Our results suggest that the downregulation expression of EAAT2 uptake, the slowdown of the Glu-Gln conversion rate, and excessively elevated Glu equilibrium concentration in astrocytes can cause an increase in Glu released from astrocytes, which results in the aggravation of epileptic seizures. Meanwhile, neuronal epileptic discharge states transition from bursting to mixed-mode spiking and tonic firing induced by the combination of these abnormal metabolism processes. This study provides a theoretical foundation and dynamical analysis methodology for further exploring the dynamics evolution and physiopathological mechanisms of epilepsy.