Contribution of the Na-K-Cl cotransporter on GABA_A receptor-mediated presynaptic depolarization in excitatory nerve terminals

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_A receptor-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.