A Computational Model Of Ph Dynamics Within The Cleft Of Conventional Neuronal Synapses

Neurotransmission is highly sensitive to the pH of the extracellular milieu. This is readily evident in the neurological symptoms that accompany systemic acid/base imbalances. Imaging data from sensory ribbon-type synapses show that neurotransmission itself can acidify the synaptic cleft, likely due to the co-release of protons, glutamate and ATP. It is not clear if the pH changes within the cleft of conventional neuronal synapses, but if it does it would provide for an additional layer of activity-dependent modulation of neurotransmission. We used a fluorescence imaging approach to examine pH dynamics within the synaptic cleft of conventional neuronal synapses and were surprised to observe alkalinization, rather than acidification, at both the Drosophila neuromuscular junction and mouse calyx of Held synapses. In an attempt to understand the difference between sensory ribbon-type synapses and conventional neuronal synapses we employed a reaction-diffusion scheme implemented in a MATLAB environment. It accommodated bicarbonate and phosphate buffering systems to model the release of protons, glutamate and ATP from synaptic vesicles, and the resulting pH dynamics within the synaptic cleft. Removal of protons across the postsynaptic membrane via the plasma membrane Ca2+-ATPase was also incorporated into the model. The model predicted acidification at conventional neuronal synapses, but only at sites of exocytosis and only for fractions of a millisecond, followed by net cleft alkalinization over tens of milliseconds. The model output is therefore consistent with our empirical data that failed to show any signs of cleft acidification, but rather revealed overall alkalinization of the cleft. The difference between sensory ribbon-type synapses and conventional neuronal synapses is attributed to the relatively low probability of release from release sites at conventional neuronal synapses and the strong alkalinizing influence of the PMCA in the postsynaptic membrane.