Synaptic Facilitation Enhances the Reliability and Precision of High-Frequency Neurotransmission

The small and tortuous volume of synaptic clefts limits the diffusion of Ca²⁺ ions during high-frequency spiking. Extracellular Ca²⁺ levels ([Ca²⁺]_o) of 0.8 mM or lower have been measured or calculated for different synapses. Here, we recorded evoked postsynaptic potentials (EPSPs) and action potentials (APs) from young-adult male and female mouse auditory brainstem principal neurons to investigate the relationship between neurotransmission reliability, stimulation frequency, and [Ca²⁺]_o In 0.8 mM [Ca²⁺]_o, we observed AP failures during stimulation at 100 Hz. Surprisingly, AP failures, EPSP-AP latency, and jitter were all reduced when stimulation frequency was increased to 500 Hz. Analysis of the EPSP revealed marked facilitation at 500 Hz that was not present at 100 Hz. Raising [Ca²⁺]_o to 1.2 mM or 2.0 mM reduced or eliminated facilitation, and, in these conditions that promote EPSP short-term depression, stimulation at 500 Hz increased the number of AP failures. In 0.8 mM Ca²⁺, stimulation over a range of frequencies from 10 to 1000 Hz produced heterogeneous frequency responses. Some principal neurons were unable to evoke fail-safe AP firing during low-frequency stimulation (10-100 Hz) but exhibited reliable firing at 300-500 Hz, which was rapid enough to activate EPSP facilitation. At frequencies above 600 Hz, all synapses began to express intermittent transmission failures. We conclude that synaptic facilitation can produce bandpass filtering in firing probability and contribute positively to the maintenance of reliable and precise high-frequency neurotransmission in calyx of Held synapses.