Epileptogenesis as a Multilevel Process: Cellular, Circuit, and Network Mechanisms

Abstract

Epileptogenesis represents the gradual transformation of the brain from a normal to a chronically hyperexcitable and hypersynchronous state. This paper proposes a unified multilevel framework describing epileptogenesis as a hierarchical and dynamic process spanning molecular, cellular, circuit, and network domains. At the molecular level, dysregulation of ion channels, neurotransmitter receptors, and chloride homeostasis disrupts excitability. At the cellular level, altered synaptic transmission, receptor trafficking, and maladaptive plasticity reinforce hyperexcitability and disinhibition. At the circuit level, microcircuit reorganization—through interneuron loss, mossy fiber sprouting, and impaired feedback inhibition—produces local oscillatory instability. At the network level, large-scale reconfiguration of functional connectivity and synchronization transforms regional disturbances into global epileptic dynamics. Glial and immune mechanisms modulate these processes by shaping extracellular homeostasis, inflammation, and blood–brain barrier integrity. Across these layers, feedback loops couple molecular defects with network behavior, producing self-reinforcing cycles of excitation and maladaptive remodeling. Temporally, epileptogenesis progresses through acute, latent, and chronic phases, each characterized by distinct but interconnected processes. The paper synthesizes these mechanisms into a cascade model emphasizing cross-scale feedback, critical transitions, and loss of resilience as defining features. This integrative perspective reframes epilepsy not as a static condition of recurrent seizures but as a systems-level reorganization driven by multilevel interactions. Mechanism-based classification and intervention strategies are discussed, emphasizing the transition from symptomatic control to causal correction. By linking molecular neurobiology, synaptic physiology, and network theory, the paper advances a comprehensive conceptual architecture for understanding, preventing, and reversing epileptogenesis.