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GABA is the major inhibitory neurotransmitter in the mature CNS. When GABAA receptors are activated the membrane potential is driven towards hyperpolarization due to chloride entry into the neuron. However, chloride ion dysregulation that alters the ionic gradient can result in depolarizing GABAergic post-synaptic potentials instead. In this review, we highlight that GABAergic inhibition prevents and restrains focal seizures but then reexamine this notion in the context of evidence that a static and/or a dynamic chloride ion dysregulation, that increases intracellular chloride ion concentrations, promotes epileptiform activity and seizures. To reconcile these findings, we hypothesize that epileptogenic pathologically interconnected neuron (PIN) microcircuits, representing a small minority of neurons, exhibit static chloride dysregulation and should exhibit depolarizing inhibitory post-synaptic potentials (IPSPs). We speculate that chloride ion dysregulation and PIN cluster activation may generate fast ripples and epileptiform spikes as well as initiate the hypersynchronous seizure onset pattern and microseizures. Also, we discuss the genetic, molecular, and cellular players important in chloride dysregulation which regulate epileptogenesis and initiate the low-voltage fast seizure onset pattern. We conclude that chloride dysregulation in neuronal networks appears to be critical for epileptogenesis and seizure genesis, but feed-back and feed-forward inhibitory GABAergic neurotransmission plays an important role in preventing and restraining seizures as well. |
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