Leveraging the transient statistics of quantal content to infer neuronal synaptic transmission

Quantal parameters of synapses are fundamental for the temporal dynamics of neurotransmitter release, forming the basis of interneuronal communication. We propose a class of models that capture the stochastic dynamics of quantal content (QC) - the number of SV fusion events per action potential (AP). Considering the probabilistic and time-varying nature of SV docking, undocking, and AP-triggered fusion, we derive an exact statistical distribution for the QC over time. Analyzing this distribution at steady-state and its associated autocorrelation function, we show that QC fluctuation statistics can be leveraged for inferring key presynaptic parameters, such as the probability of SV fusion (release probability), and SV replenishment at empty docking sites (refilling probability). Our model predictions are tested with electrophysiological data obtained from 50-Hz stimulation of auditory MNTB-LSO synapses in brainstem slices of juvenile mice. Our results show that while synaptic depression can be explained by low and constant refilling/release probabilities, this scenario is inconsistent with the statistics of the electrophysiological data that show a low QC Fano factor and almost uncorrelated successive QCs. Our systematic analysis yields a model that couples a high release probability to a time-varying refilling probability to explain both the synaptic depression and its associated statistical fluctuations. In summary, we provide a general approach that exploits stochastic signatures in QCs to infer neurotransmission-regulating processes that are indistinguishable from just analyzing averaged synaptic responses.