Neural glial network instability in epilepsy

Abstract

Epilepsy is traditionally defined by recurrent seizures arising from abnormal neuronal excitability, yet growing evidence indicates that this view is incomplete. This narrative review examines epilepsy through the framework of neural–glial network instability, an integrative perspective that places neuronal dysfunction within a broader system shaped by glial regulation, calcium dysregulation, neuroinflammatory signaling, and circuit remodeling. The review first reframes epilepsy as a disorder of progressive instability in which failures of excitation–inhibition balance, extracellular homeostasis, inflammatory restraint, and adaptive plasticity shift neural networks from compensated function toward seizure-prone states. It then synthesizes neuronal mechanisms, including excitation–inhibition imbalance, GABAergic dysfunction, and altered intrinsic excitability, together with glial mechanisms involving astrocytic regulation of ionic and neurotransmitter environments, microglial inflammatory and synaptic responses, and oligodendroglial contributions to conduction and network coordination. Calcium dysregulation is considered a cross-cutting mechanism linking excitability, intracellular stress, gliotransmission, inflammation, and long-term remodeling. The review further examines how neuroinflammation and chronic circuit reorganization help convert transient disturbances into persistent epileptic networks. Together, this framework offers a more integrated account of seizure emergence, epileptogenesis, and chronic seizure susceptibility and points toward mechanism-informed therapeutic strategies aimed at restoring durable network stability.

Keywords

epilepsy / neural–glial network instability / epileptogenesis / astrocytes / microglia / calcium dysregulation / neuroinflammation / circuit remodeling

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