Evidence for an excitatory GABAA response in human motor cortex in idiopathic generalised epilepsy

• TMS was used to explore GABA-mediated inhibition in IGE.
• Post-synaptic GABAB inhibition (LICI) was normal, but pre-synaptic LICF reduced.
• GABAA inhibition (SICI) was reduced in untreated but not treated IGE.
• When tested during GABAB inhibition, the SICI protocol was excitatory.
• During ongoing GABAB inhibition, GABAA activation may be excitatory.

PurposeImpaired GABAergic inhibition has been implicated in the pathophysiology of epilepsy. The possibility of a paradoxical excitatory effect of GABA in epilepsy has been suggested, but has not been investigated in vivo. We investigated pre- and post-synaptic GABAergic mechanisms in patients with idiopathic generalised epilepsy (IGE).MethodIn 10 patients and 12 control subjects we explored short- and long-interval intracortical inhibition (SICI, LICI; post-synaptic GABAA and GABAB-mediated respectively) and long-interval intracortical facilitation (LICF; pre-synaptic disinhibition) using transcranial magnetic stimulation.ResultsWhile post-synaptic GABAB-mediated inhibition was unchanged in IGE (p = 0.09), LICF was reduced compared to controls (controls: 141 ± 17% of baseline; untreated patients: 107 ± 12%, p = 0.2; treated patients: 79 ± 10%, p = 0.003). GABAA-mediated inhibition was reduced in untreated patients (response amplitude 56 ± 4% of baseline vs. 26 ± 6% in controls, p = 0.004) and normalised with treatment (37 ± 12%, p = 0.5 vs. controls). When measured during LICI, GABAA-mediated inhibition became excitatory in untreated IGE (response amplitude 120 ± 10% of baseline, p = 0.017), but not in treated patients.ConclusionPre- and post-synaptic GABA-mediated inhibitory mechanisms are altered in IGE. The findings lend in vivo support to evidence from experimental models and in vitro studies of human epileptic brain tissue that GABA may have a paradoxical excitatory role in ictogenesis.