WONOEP XVII appraisal: Targeting network excitability beyond the synapse -Neurotransmitter, ionic, and electro -diffusions

Epilepsy affects approximately 1% of the population worldwide, and although medications are effective in the majority of cases, seizures persist in approximately 30% of patients. Despite the effort to develop new antiseizure drugs, the rate of pharmacoresistance in patients has not diminished over the past 3 decades. There is thus a real unmet need, and new approaches and therapeutic targets should be pursued. Seizures are caused by a change in neuronal excitability resulting in hyperexcitation and hypersynchronization of neurons, and modulating either intrinsic neuronal properties or synaptic transmission has been and still is the best way to reduce excitation and synchronization of the neuronal network. However, network excitability and synchronicity are also influenced by many extrasynaptic regulators. Extracellular diffusion of glutamate and γ-aminobutyric acid (GABA) and activation of their extrasynaptic receptors also participate in the generation of a hyperexcitable environment. Interestingly, even without synaptic transmission, neuronal activity can synchronize and propagate throughout the network via gap junctions, extracellular potassium ionic diffusion, and electric fields. In this review, we will discuss the recent advances in our understanding of how different extrasynaptic signaling mechanisms influence neuronal excitability and whether they could be candidate therapeutic targets to treat refractory epilepsy. This review emanated from the XVII Workshop on Neurobiology of Epilepsy meeting (Kilkea, Ireland) organized in 2023 by the Neurobiology Commission of the International League Against Epilepsy.