Abstract Body

Asynchronous release (AR) of neurotransmitter is a characteristic feature of some synapses in the CNS and neuromuscular junctions. In addition, AR becomes more pronounced during neurodegenerative disorders. Therefore, analysis of the mechanisms underlying AR is critical for a better understanding of normal and pathological brain functioning. One of the CNS synapses that possess pronounced asynchronous release is a synapse formed by hippocampal CCK-positive interneurons on the CA1 pyramidal neurons. Here, we propose a computational model of asynchronous release in this synapse. The model incorporates biophysically realistic dynamics of intraterminal Ca²⁺ and Na⁺ concentration with dynamics of synaptic vesicle release in the axonal bouton of CCK-positive interneurons, which enables us to fit model parameters based on the data of experiments in which we modulated Ca²⁺/Na⁺ dynamics. In particular, we studied the dependence of asynchronous release on the activity of plasmalemmal Na⁺/Ca²⁺ exchanger (NCX), the activity of plasma membrane Ca²⁺ pump (PMCA), and the presence of EGTA in the terminal. The proposed model was able to reproduce all the data obtained on the dynamics of asynchronous release in the studied synapse. The obtained results suggest that NCX serves as an essential source of Ca2+ during a long train of action potentials, therefore Na+ dynamics can play an important role in the asynchronous release.