Computational modeling predicts ephemeral acidic microdomains in the glutamatergic synaptic cleft

Area of Science:

• Neuroscience
• Biophysics
• Computational Biology

Background:

• Chemical synapses are expected to acidify due to the release of acidic contents from synaptic vesicles.
• Experimental data from fluorescent pH probes show synaptic cleft alkalinization, contradicting this expectation.

Purpose of the Study:

• To model the pH dynamics at the Drosophila neuromuscular junction following neurotransmitter release.
• To explain the observed synaptic cleft alkalinization using a reaction-diffusion model.

Main Methods:

• Developed a reaction-diffusion model for pH dynamics at the Drosophila neuromuscular junction.
• Incorporated neurotransmitter release (glutamate, ATP, H+), buffering systems (bicarbonate, phosphate), and plasma membrane calcium-ATPase (PMCA) activity.
• Simulated pH changes over time following simulated neurotransmitter release.

Main Results:

• The model predicted a transient cleft acidification lasting milliseconds, followed by rapid and sustained alkalinization over 100 ms.
• Plasma membrane calcium-ATPase activity was identified as the primary driver of cleft alkalinization by removing protons (H+).
• Buffering systems and cleft volume significantly influenced pH transient magnitude and duration, with structural features impacting pH transients.

Conclusions:

• The model successfully recapitulates experimental observations of synaptic cleft alkalinization.
• PMCA activity is crucial for the rapid and prolonged alkalinization of the synaptic cleft post-neurotransmission.
• Synaptic cleft geometry and buffering capacity play significant roles in modulating pH dynamics during synaptic transmission.