Impaired state-dependent potentiation of GABAergic synaptic currents triggers seizures in an idiopathic generalized epilepsy model

Idiopathic generalized epilepsy(IGE) patients have genetic causes and their seizure onset mechanisms particularly during sleep remain elusive. Here we proposed that sleep-like slow-wave oscillations(0.5 Hz SWOs) potentiated excitatory or inhibitory synaptic currents in layer V cortical pyramidal neurons from wild-type(wt) mouse ex vivo brain slices. In contrast, SWOs potentiated excitatory, not inhibitory, currents in cortical neurons from heterozygous(het) knock-in(KI) IGE mice(GABAA receptor lower case Greek gamma2 subunit Gabrg2Q390X mutation), creating an imbalance between evoked excitatory and inhibitory currents to effectively prompt neuronal action potentials. Similarly, more physiologically similar up/down-state(present during slow-wave sleep) induction in cortical neurons could potentiate excitatory synaptic currents within slices from wt/het Gabrg2Q390X KI mice. Consequently, SWOs or up/down-state induction in vivo (using optogenetic method) could trigger epileptic spike-wave discharges(SWDs) in het Gabrg2Q390X KI mice. To our knowledge, this is the first operative mechanism to explain why epileptic SWDs preferentially happen during non-REM sleep or quiet-wakefulness in human IGE patients.