Schematic depiction of simple models through which dysregulation of GABAA receptor-mediated inhibition can increase the activity of neuronal networks, potentially generating seizures. GABA inhibition can fail when GABA or GABAA receptor expression is low, when GABA depolarizes neurons, or when miswiring and mistargeting of synapses occur. Excessive GABA inhibition may trigger seizures by disinhibiting target cells, or via excessive synchronization of the neurons in the epileptogenic focus. Please note that the effects of dysregulated GABA signaling in more complex neuronal networks, especially in the presence of abnormal circuitry or with specific pathologies, may differ. In such cases a combination of the above models may be applicable at different sites of the epileptogenic network rendering the pharmacological effect of a GABAergic agonist not completely predictable by a single model. Furthermore, shunting inhibition may explain situations where GABAergic drugs silence excessive excitatory network activity, in neurons with depolarizing GABAergic signaling.
