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

Abstract

GABA_A 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 GABA_A receptor actions on glutamatergic presynaptic nerve terminals projecting to ventromedial hypothalamic (VMH) neurons. The activation of presynaptic GABA_A 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 GABA_A 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, GABA_Areceptor-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.