Information Processing at the Calyx of Held Synapse Under Natural Conditions

This study investigates the role of the medial nucleus of the trapezoid body (MNTB) in sound processing. The experimental part focuses on in vitro experiments in acute brain slices of Mongolian gerbils, in parallel a theoretical approach explains the experimental results in the context of a mathematical vesicle-release model. One of the hallmarks of auditory neurons in vivo is spontaneous activity that occurs even in the absence of any sensory stimuli. Sound evoked bursts of discharges are thus embedded within this background of random firing. The calyx of Held synapse has been characterized in vitro as a fast relay that reliably fires at high stimulus frequencies (up to 800 Hz). However, inherently due to the preparation method, spontaneous activity is absent in studies using brain slices. This study deals with the question how this ongoing activity is influencing synaptic transmission. The answer is divided into three parts. In the first part a phenomenological description of the effects of spontaneous activity on synaptic transmission is given. Therefore in vivo spontaneous firing rates were determined and then reintroduced as random firing patterns to in vitro brain stem synapses. After conditioning synapses for two minutes at Poisson averaged rates of 20, 40, and 60 Hz, a number of differences in synaptic transmission were observed. Accordingly, current-clamp, dynamic-clamp, and loose-patch recordings revealed a number of failures at the postsynaptic cell, although the initial onset of evoked activity was still transmitted with higher fidelity. The conclusion of these observations is that in vivo auditory synapses are in a tonic state of reduced EPSCs as a consequence of spontaneous spiking. In the second part the conditioned state of calyx of Held synapse is closer investigated by modeling the short-term dynamics with a biophysically motivated vesicle release model. The mechanisms regulating short-term plasticity can be demonstrated in physiological studies as well as computer models aimed at testing the functional role of them. In the case of the calyx of Held synapse, considerable progress has been made in understanding the dynamics of transmission both on a physiological and modeling level. Nevertheless, little is known about the processing of complex, long lasting stimulation patterns mimicking the input typically present in the intact brain. Furthermore, calyx of Held synapses are chronically active in vivo due to spontaneous activity in the auditory brainstem. Here we test synaptic responses to complex stimulation protocols mimicking periods of low and high activity, as well as protocols derived from natural sound clips. Additionally, all stimuli were embedded in chronic background activity attempting to imitate the naturally occurring spontaneous activity. We measured synaptic responses to these stimulus trains and then used the data to test how well several vesicle-release models could capture the dynamics observed physiologically. Already the most basic model variant produced very good results with correlation coefficients between the experimental data and the model prediction of more than 90%. None of the more complex model variants, which incorporated additional physiological effects, could improve this prediction accuracy significantly. The conclusion of these results is that the functional state of chronically active calyces differs from the functional state of silent calyces, and that this chronically active functional state can be described in simpler terms. Finally the third part focuses on the transition phase between completely rested synapses and synapses conditioned with simulated spontaneous activity. Modeling the transition phase at the beginning of the conditioning period reveals significant changes in the model parameters thus suggesting changes in the underlying biophysical parameters including the vesicle pool size and the release probability. Recovery experiments after switching off the spontaneous activity confirm the reduced pool size and show a very slow recovery on a time scale of minutes. This slow recovery is accompanied by a reduction in the frequency of miniature EPSCs, a measure for the concentration of calcium ions in the presynaptic terminal. The observed changes again confirm the finding that synapses under the influence of ongoing activity show different properties than completely rested synapses. Overall the results of this study show that spontaneous activity has significant influences on the synaptic dynamics of cells in the MNTB. The point of view that the calyx of Held is not just a relay station transforming excitatory input into inhibitory output is further strengthened, and this has consequences for the encoding of signals throughout the auditory pathway.