Autocrine boost of NMDAR current in hippocampal CA1 pyramidal neurons by a PMCA-dependent, perisynaptic, extracellular pH shift

Abstract

The plasma membrane Ca2+-ATPase (PMCA) is found near postsynaptic NMDARs. This transporter is a Ca2+-H+exchanger that raises cell surface pH.Wetested whether thePMCAacts in an autocrine fashion to boost pH-sensitive, postsynapticNMDARcurrents. In mouse hippocampal slices, NMDAR EPSCs in a singly activated CA1 pyramidal neuron were reduced when buffering was augmented by exogenous carbonic anhydrase (XCAR). This effect was blocked by the enzyme inhibitor benzolamide and mimicked by the addition of HEPES buffer. Similar EPSC reduction occurred whenPMCAactivation was prevented by dialysis ofBAPTAor thePMCAinhibitor carboxyeosin. Using HEPES, BAPTA, or carboxyeosin, the effect ofXCARwas completely occluded.XCARsimilarly curtailedNMDAREPSCs of minimal amplitude, but had no effect on small AMPAR responses. These results indicate that a significant fraction of the postsynaptic NMDAR current is reliant on a perisynaptic extracellular alkaline shift generated by the PMCA.