Synaptic glutamate release is modulated by the Na+ -driven Cl-/HCO₃⁻ exchanger Slc4a8

J Neurosci. 2011 May 18;31(20):7300-11. doi: 10.1523/JNEUROSCI.0269-11.2011.


On the one hand, neuronal activity can cause changes in pH; on the other hand, changes in pH can modulate neuronal activity. Consequently, the pH of the brain is regulated at various levels. Here we show that steady-state pH and acid extrusion were diminished in cultured hippocampal neurons of mice with a targeted disruption of the Na(+)-driven Cl(-)/HCO(3)(-) exchanger Slc4a8. Because Slc4a8 was found to predominantly localize to presynaptic nerve endings, we hypothesize that Slc4a8 is a key regulator of presynaptic pH. Supporting this hypothesis, spontaneous glutamate release in the CA1 pyramidal layer was reduced but could be rescued by increasing the intracellular pH. The reduced excitability in vitro correlated with an increased seizure threshold in vivo. Together with the altered kinetics of stimulated synaptic vesicle release, these data suggest that Slc4a8 modulates glutamate release in a pH-dependent manner.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Cells, Cultured
  • Chloride-Bicarbonate Antiporters / physiology*
  • Female
  • Glutamic Acid / metabolism*
  • Hydrogen-Ion Concentration
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Patch-Clamp Techniques
  • Sodium / metabolism*
  • Sodium-Bicarbonate Symporters / deficiency
  • Sodium-Bicarbonate Symporters / genetics
  • Sodium-Bicarbonate Symporters / physiology*
  • Synapses / metabolism*


  • Chloride-Bicarbonate Antiporters
  • SLC4A8 protein, mouse
  • Sodium-Bicarbonate Symporters
  • Glutamic Acid
  • Sodium