The Na⁺/H⁺ exchanger is a major pH regulator in GABAergic presynaptic nerve terminals synapsing onto rat CA3 pyramidal neurons

The effects of pH_i on GABAergic miniature inhibitory postsynaptic currents (mIPSCs) were studied in mechanically dissociated CA3 pyramidal neurons, by use of ammonium prepulse and whole-cell patch-clamp techniques, under the voltage-clamp condition. NH₄Cl itself, which is expected to alkalinize pH_i, increased GABAergic mIPSC frequency in a concentration-dependent manner. In contrast, NH₄Cl decreased mIPSC frequency, either in the presence of 200 μm Cd²⁺ or in Ca ²⁺-free external solution, suggesting that intraterminal alkalosis decreased GABAergic mIPSC frequency while [NH4⁺] itself may activate Ca²⁺ channels by depolarizing the terminal. On the other hand, GABAergic mIPSC frequency was greatly increased immediately after NH ₄Cl removal, a condition expected to acidify pH_i, and recovered to the control level within 2 min after NH₄Cl removal. This explosive increase in mIPSC frequency observed after NH₄Cl removal was completely eliminated after depletion of Ca²⁺ stores with 1 μm thapsigargin in the Ca²⁺-free external solution, suggesting that acidification increases in intraterminal Ca²⁺ concentration via both extracellular Ca²⁺ influx and Ca²⁺ release from the stores. However, the acidification-induced increase in mIPSC frequency had not recovered by 10 min after NH₄Cl removal either in the Na ⁺-free external solution or in the presence of 10 μm 5-(N-ethyl-N-isopropyl)-amiloride (EIPA), a specific Na⁺/H ⁺ exchanger (NHE) blocker. The present results suggest that NHEs are major intraterminal pH regulators on GABAergic presynaptic nerve terminals, and that the NHE-mediated regulation of pH_i under normal physiological or pathological conditions might play an important role in the neuronal excitability by increasing inhibitory tones.