Consequences of decoy site repair and feedback regulation on neurotransmission dynamics

Neurons form the fundamental unit of the central nervous system with the human brain containing close to 100 billion neurons. We present a systems-level model of a chemical synapse by which signals from a presynaptic neuron are transmitted to a postsynaptic neuron. In this model, neurotransmitter-filled synaptic vesicles (SVs) dock with a given rate at a fixed number of docking sites in the axon terminal of the presynaptic neuron. Upon the arrival of an action potential (AP), each docked SV has a certain probability to fuse with the presynaptic membrane and release neurotransmitters into the synaptic cleft. After the SV fusion event, the corresponding docking site undergoes repair before becoming available to be reoccupied by an SV. We develop a stochastic model of these coupled processes and derive exact analytical results quantifying the mean and the degree of random fluctuations (i.e., noise) in the levels of docked SVs and released neurotransmitters in response to a train of APs. Our results show that the repair of docking sites exacerbates synaptic depression, i.e., reduces the ability of the chemical synapse to release neurotransmitters in response to an AP. Moreover, repair amplifies statistical fluctuations in neurotransmission for fixed mean neurotransmitter levels. We next consider feedback regulation where the released neurotransmitters affect the rate of SV docking. Counterintuitively, our analysis reveals that for certain physiological parameter spaces, positive feedback loops can reduce noise levels in both the number of docked SVs and neurotransmitters in the cleft.