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.