pH transients evoked by excitatory synaptic transmission are increased by inhibition of extracellular carbonic anhydrase.

Excitatory synaptic transmission has been associated with a rapid alkalinization of the brain extracellular space. These pH shifts are markedly increased by acetazolamide, an inhibitor of carbonic anhydrase. Although this effect can be readily explained by inhibition of extracellular carbonic anhydrase, this enzyme has been considered strictly intracellular in the central nervous system. To determine whether these alkaline shifts are regulated by extracellular carbonic anhydrase, we studied the effects of a membrane impermeant, dextran-bound inhibitor of this enzyme. Extracellular alkaline transients, measured with pH-sensitive microelectrodes, were generated in the CA1 region of rat hippocampal slices by repetitive electrical stimulation of Schaeffer collateral fibers or by local ejection of glutamate. More direct alkalinizations were elicited by focal ejection of NaOH in the vicinity of a pH microelectrode. These pH transients were reversibly enhanced by addition of the dextran-bound inhibitor. We conclude that there is significant carbonic anhydrase activity in the extracellular space of the brain. We postulate that this enzyme functions in the regulation and modulation of extracellular pH transients associated with neuronal activity.