Synaptic facilitation enhances the reliability and precision of high frequency neurotransmission

Abstract

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 (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 [Ca2+]o. In 0.8 mM [Ca2+]o, we observed AP failures during afferent fiber stimulation at 100 Hz. Surprisingly, AP failures, EPSP-AP latency and jitter were all greatly reduced when stimulation frequency was increased to 500 Hz. Analysis of the EPSP/AP waveform 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, stimulation at 500 Hz increased the number of AP failures. In 0.8 mM [Ca2+]o, afferent fiber stimulation over a broad range of frequencies from 10-1000 Hz produced three different types of spiking responses: Type I cells exhibited band-pass filtering, with best response at approximately 500 Hz, Type II cells exhibited low-pass filtering above 600 Hz, and Type III cells exhibited shallow band-pass filtering centered at approximately 300 Hz. To predict AP success or failure, we built a model based on three factors: size of the EPSP, membrane potential immediately prior to the synaptic event and the number of preceding failures. We conclude that synaptic facilitation can contribute positively to the maintenance of reliable and precise high frequency neurotransmission in the auditory brainstem. Significance StatementFacilitation 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 Ca2+ concentration ([Ca2+]o). Physiological levels of [Ca2+]o can vary from 0.8 to 1.2 mM depending on synaptic activity. In the mouse Medial Nucleus of the Trapezoid Body, synaptic facilitation is readily observable in slice experiments using relatively low (0.8 mM) [Ca2+]o, but is partially or completely obscured by short-term synaptic depression when [Ca2+]o is high (1.2 or 2.0 mM). Here we show that facilitation can rescue the reliability of high-frequency (500 Hz) action potential firing in low [Ca2+]o, resulting in band-pass filter transmission.