Impact of distinct neurotransmitter release modes on neuronal signaling

Abstract Neuronal communication is governed by a diverse repertoire of neurotransmitter release modes, each with distinct molecular machinery and functional roles. Beyond rapid, high-fidelity synchronous release, asynchronous release supports sustained neurotransmitter output, while spontaneous, action-potential-independent release plays a critical role in synaptic development, homeostasis, and plasticity. Complementing these forms of release, slow neurotransmission mediated by monoamines and neuropeptides acts over longer timescales to shape network-wide activity. This review explores the unique mechanisms of each mode, highlighting compelling evidence that spontaneous and evoked release are functionally segregated through separate vesicle pools and distinct postsynaptic receptors. We also examine the molecular complexity and debated physiological roles of asynchronous release, particularly at excitatory synapses, and the specialized machinery of neuromodulatory systems. A comprehensive understanding of these varied release mechanisms is fundamental to neuroscience and opens novel therapeutic avenues. Targeting the unique molecular components of each release mode offers a promising strategy for developing more precise treatments for neurological and psychiatric disorders.