Glutamate receptor-dependent cytosolic acidification in hippocampal neurons involves passive flux of protons from the extracellular space

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Abstract Glutamate receptor-dependent cytosolic acidification can be induced in hippocampal neurons by pharmacological or seizure-like stimulation. This acidification is thought to arise from Ca 2+ and metabolism-related processes, however, the exact underlying mechanism as well as its functional role remains uncertain. To reassess the mechanism of cytosolic acidification in excitatory hippocampal neurons and address the physiological relevance of the phenomenon, we combined pH/Ca 2+ biosensors to study activity-induced pH dynamics in hippocampal neurons. First, we addressed cytosolic acidification in relation to LTP at hippocampal CA3-CA1 synapses. Using hippocampal slices from adult rats of both sexes, we show that LTP-inducing stimulation at the Schaffer collaterals evokes transient cytosolic acidification in hippocampal CA1 neurons. This highlights neuronal pH shifts as a trait of general hippocampal neurotransmission rather than a marker of excitotoxicity, possibly serving as a secondary messenger. Moreover, using dissociated hippocampal neurons from rat embryos, we show that glutamate receptor agonists typically induce larger cytosolic acid shifts compared to simple depolarization or spontaneous activity, suggesting that glutamate receptor-mediated acidification involves several separate mechanisms; pyruvate-dependent dampening of neuronal acidification may reflect a direct inhibition of NMDA receptors rather than reduced glycolytic activity, questioning the previously reported involvement of metabolism in cytosolic acidification; and whereas acid shifts induced by simple depolarization show exclusive dependence on cytosolic Ca 2+ , AMPA-induced acidification depends both on cytosolic Ca 2+ and on an inward electrochemical driving force for protons. These results suggest that glutamate receptor-induced cytosolic acidification relies both on cytosolic Ca 2+ and on a passive proton influx, possibly mediated by the receptor itself. Graphical abstract Significance statement Although several studies report that hippocampal pyramidal neurons show significant cytosolic acidification in response to activation by drugs, epilepsy and stroke, the molecular mechanism and functional impact of the phenomenon remains uncertain. Using live imaging of both Ca and H dynamics, we demonstrate that the induction of LTP at hippocampal synapses is associated with cytosolic acidification in the postsynaptic neurons, suggesting that the cytosolic acid shifts may be a general trait of neurotransmission and related plasticity. We further revisit the mechanistic relation between the two ion systems. Our results suggest that glutamate receptor-induced cytosolic acidification involves two distinct mechanisms, one related to cytosolic Ca and another involving a passive H influx, possibly mediated by the receptor itself.

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