Tahere Mohammadpour, Reza Mohammadzadeh
Epilepsy is a complex neurological disorder characterized by recurrent seizures resulting from an imbalance between excitatory and inhibitory neurotransmission. γ-Aminobutyric acid type A receptors (GABAARs), the principal mediators of fast inhibitory synaptic transmission, are essential for maintaining neuronal stability. Their function depends on tightly regulated trafficking processes, including subunit assembly in the endoplasmic reticulum, transport through the Golgi apparatus, membrane insertion, synaptic targeting, stabilization, and recycling. Disruptions in these processes, caused by genetic mutations, aberrant posttranslational modifications, or seizure-induced neuronal activity, impair receptor surface expression and localization, reducing inhibitory signaling and promoting network hyperexcitability. Evidence from human and animal studies indicates that altered GABAAR trafficking contributes to epileptogenesis and pharmacoresistance, particularly during severe conditions such as status epilepticus. Understanding the molecular mechanisms regulating GABAAR trafficking provides insights into epilepsy pathophysiology and highlights potential therapeutic strategies aimed at restoring inhibitory balance. By linking these trafficking mechanisms to synaptic structure and ion channel function, this review situates GABAAR biogenesis within the broader framework of synaptic organization relevant to epilepsy and other neurological disorders.