The small and tortuous volume of synaptic clefts limits the diffusion of Ca 2+ ions during high frequency spiking. Extracellular Ca 2+ levels (Ca 2+ o ) of 0.8 mM or lower have been measured or calculated for different synapses. Here, we recorded evoked postsynaptic potentials (EPSP) and action potentials (AP) from young adult male and female mouse auditory brainstem principal neurons to investigate the relationship between neurotransmission reliability, stimulation frequency and Ca 2+ o . In 0.8 mM Ca 2+ 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 Ca 2+ 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 Ca 2+ , stimulation over a range of frequencies from 10-1000 Hz produced heterogenous 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. Significance Statement Facilitation of evoked postsynaptic currents is a common feature of synapses. The strength of facilitation and its role in reaching spike threshold depends on intrinsic properties of the synapse, stimulation frequency, and extracellular Ca 2+ concentration (Ca 2+ o ). Physiological levels of Ca 2+ o can vary from 0.8 to 1.2 mM depending on synaptic activity. In auditory calyx-type synapses, synaptic facilitation is readily observable in brainstem slices using relatively low (0.8 mM) Ca 2+ o , but is partially or completely obscured by short-term synaptic depression when Ca 2+ o is higher (1.2 or 2.0 mM). Here we show that short-term synaptic facilitation can rescue the reliability of high-frequency (500 Hz) action potential firing in low Ca 2+ o .
Correa et al. (Wed,) studied this question.