Cellular ion homeostasis and pH regulation critically depend on the activity of ion exchangers. This is of special importance in the brain, where pH modulates neuronal excitability and neuronal activity in turn can cause changes in pH. The objective of our studies were the investigation of the physiological function of the Na+-coupled anion-exchanger Slc4a8 in the mammalian brain, as well as a comparative analysis of the closely related transporter Slc4a10 with the help of knockout mouse models. Both anion exchanger are expressed broadly in neurons. Supporting an important role of Slc4a8 for neuronal pH regulation, cultured hippocampal neurons of mice with a targeted disruption of Slc4a8 showed a reduced steady-state pHi and recovered more slowly from an acute acid load. In accordance with enrichment of Slc4a8 in presynaptic nerve endings of pyramidal neurons, the electrophysiological analysis revealed a pH-dependent presynaptic defect with impaired glutamate release. Whereas, release of the inhibitory neurotransmitter GABA was not affected. The decrease of hippocampal excitability in Slc4a8-/- slices in vitro was reflected by an increased seizure threshold in vivo. Accordingly, these results of our studies propose that Slc4a8 in the brain modulates glutamate release and thus synaptic strength in a pH-dependent way. In contrast, Slc4a10 shows a distinct neuronal expression, partly overlapping but mostly amendatory to Slc4a8. The newest results of our group suggest a crucial role of Slc4a10 for GABAergic inhibition. Thus, these results suggest important roles of Slc4a8 and Slc4a10 for brain function and support their importance as possible targets for clinical applications e.g. in the future treatment of epilepsy.