Chloride's Exciting Role in Neonatal Seizures Suggests Novel Therapeutic Approach

Commentary Inhibition in the central nervous system is dependent on chloride conductance through GABAA receptor-associated channels. When chloride channels open, the membrane potential is driven toward chloride’s reversal potential, and because chloride’s reversal potential is negative to the neuron’s threshold for firing action potentials, it normally has an inhibitory effect. GABAA receptors have binding sites for both barbiturates and benzodiazepines, allowing them to enhance the inhibitory effect of GABA at this receptor; it is this mechanism of action that is responsible for the anticonvulsant activity of these agents. Prolonged seizure activity reduces the efficacy of GABAergic antiepileptic drugs (AEDs) such as benzodiazepines and barbiturates. If postsynaptic GABAA receptor responsiveness was reduced, one would expect GABAergic agents to lose efficacy as well. Indeed, a gradual suppression of GABAA receptor responses occurs during in vitro kindling (1) and GABA receptor internalization during ongoing seizures and status epilepticus has been documented (2), accounting for pharmacoresistance to GABAergic agents in these settings. One might also expect reduced inhibitory efficacy to result from intracellular buildup of chloride: prolonged neuronal activity results in elevated extracellular potassium concentrations, and this potassium is cleared in part by neuronal transporters that bring potassium back into the cells. NKCC1 is one such transporter, and when this transporter brings potassium back into the cells, it imports chloride with it. The resultant elevation of intracellular chloride will reduce efficacy of GABAA receptor-mediated synaptic inhibition by making the chloride reversal potential less negative. However, in the mature nervous system, the KCC2 transporter will do its best to counteract this chloride buildup by extruding chloride and restoring normal homeostasis. In the immature nervous system, however, the KCC2 transporter is not fully expressed. This makes the neonate more vulnerable to intracellular chloride buildup mediated by the NKCC1 transporter. Indeed, immature neurons have elevated baseline concentrations of intracellular chloride; as a result, neonatal GABAA receptor responses are not only less inhibitory, they may actually be excitatory (3, 4). The excitatory action of GABA-mediated chloride conductance is believed to contribute to the increased incidence of seizures in human neonates (5). There is a progressive developmental increase in expression of the chloride-extruding transporter KCC2 in the brain that eventually allows for the full expression of hyperpolarizing GABAA receptor responses; in the rat hippocampus, this occurs by the end of the second postnatal week (6). Numerous experiments have been done examining the efficacy of barbiturates in neonatal seizure models in vitro and in vivo, with conflicting results (7, 8). The current paper by Dzhala and colleagues attempts to make sense of this controversial area of investigation. The authors propose that the differences in response to GABAergic AEDs may correlate with Progressive NKCC1-Dependent Neuronal Chloride Accumulation During Neonatal Seizures.