Adverse Outcome Pathway on binding to the picrotoxin site of ionotropic GABA receptors leading to epileptic seizures in adult brain

This AOP begins with the interaction of chemicals to the picrotoxin binding site of the ionotropic GABA receptor complex causing blockage of the ion channel. As a result, decrease in inward chloride conductance occurs, followed by a reduction in postsynaptic inhibition, reflected as reduced frequency and amplitude of spontaneous inhibitory postsynaptic current or abolishment of GABA-induced firing action. Consequently, the resistance of excitatory neurons to fire is decreased, resulting in the generation of a large excitatory postsynaptic potential (EPSP) that causes voltage-gated Na⁺ to open, which results in action potentials. The depolarisation is followed by a period of hyper-polarisation mediated by Ca²⁺-dependent K⁺ channels or GABA-activated Cl⁻ influx, which becomes smaller, gradually disappears, and is replaced by a depolarisation known as “paroxysmal depolarizing shift” (PDS). A PDS is an indication of epilepsy at the cellular level and initiates the adverse outcome at the organismal level of epileptic seizure.