Non-synaptic GABA release as a trigger for synchronous epileptiform network patterns

The mechanisms leading to the onset of a focal seizure are still not understood. Experimental data in animal models and patients suggest that both interneurons and principal cells contribute to focal seizure generation. We investigate here whether neurons are driven by non-synaptic γ-aminobutyric acid (GABA) release during seizures generated in models of focal ictogenesis.

We used the well-established 4-aminopyridine (4AP) seizure model to analyze epileptiform discharges in naïve mouse entorhinal cortex slices and in guinea pig brains maintained in vitro. Pharmacological dissection of epileptiform events was performed during simultaneous field potential and patch-clamp recordings.

4AP (100 μM) elicited periodic and large chloride currents in both principal neurons and GABAergic interneurons that steadily matched simultaneously recorded interictal population spikes. These population spike-associated chloride currents (PSACC) (i) survived glutamate receptor blockade, (ii) were abolished by GABA_A antagonists and by blocking the synaptic neurotransmitters release, (iii) were reduced by excitatory amino acid transporter antagonist, and (iv) were enhanced by GABA transporter 1 antagonist. Application of the antagonist of bestrophin-1 (BEST-1) channels inhibited both PSACCs and the associated spikes and prevented the occurrence of seizure-like events in entorhinal cortex mouse slices and in the isolated guinea pig brain.

We propose that GABA released via bestrophin-1 channels induces large and synchronous chloride currents in principal cells and interneurons, and establishes the conditions for the generation of seizure-like events. We propose that neuronal epileptiform discharges are generated by fast transmembrane ion changes imposed by non-vesicular GABA release, possibly sustained by astrocytes.