Contribution of the Na–K–Cl Cotransporter on GABAAReceptor-Mediated Presynaptic Depolarization in Excitatory Nerve Terminals

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Abstract
GABAA receptor-mediated responses manifest as either hyperpolarization or depolarization according to the intracellular Cl− concentration ([Cl−]i). Here, we report a novel functional interaction between the Na–K–Cl cotransporter (NKCC) and GABAA receptor actions on glutamatergic presynaptic nerve terminals projecting to ventromedial hypothalamic (VMH) neurons. The activation of presynaptic GABAA receptors depolarizes the presynaptic nerve terminals and facilitates spontaneous glutamate release by activating TTX-sensitive Na+ channels and high-threshold Ca2+ channels. This depolarizing action of GABA was caused by an outwardly directed Cl− driving force for GABAA receptors; that is, the [Cl−]i of glutamatergic nerve terminals was higher than that predicted for a passive distribution. The higher [Cl−]i was generated by bumetanide-sensitive NKCCs and was responsible for the GABA-induced presynaptic depolarization. Thus, GABAAreceptor-mediated modulation of spontaneous glutamatergic transmission may contribute to the development and regulation of VMH function as well as to the excitability of VMH neurons themselves.