Shifts in the local pH occur in the brain during normal function, and both intracellular and extracellular pH shifts are caused by neuronal firing. This correlation between pH shifts and neuronal hyperactivity is well established, but examining the underlying events in detail is difficult because the systems to measure the extracellular H+ concentration are not accurate. On page 1435, the team led by Fabio Benfenati and Fabrizia Cesca set out to describe the spatio-temporal dynamics of pH-induced modulation of neural excitability. The authors first engineered ex.E2GFP, a genetically encoded ratiometric biosensor that is specifically sensitive to acidic pH shifts and targeted to the extracellular side of the plasma membrane. Monitoring real-time variations of E2GFP fluorescence in primary hippocampal neurons then allows the quantification of pH fluctuations during hyperactivity of the neuronal network. The authors show that sustained hyperactivity causes a decrease in pH that is localised to active synapses. This extracellular pH shift is not attributable to the outflow of intravesicular protons into the cleft during intense exocytosis, but rather to activation of the Na+/H+ exchanger. The data obtained from the use of this new extracellular sensor demonstrate that an extracellular synaptic pH shift occurs during epileptic-like activity of neural cultures, and emphasise the strict links between synaptic activity and synaptic pH.
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