Wiring and Volume Transmission: An Overview of the Dual Modality for Serotonin Neurotransmission

Serotonin is a neurotransmitter involved in the modulation of a multitude of physiological and behavioral processes. In spite of the relatively reduced number of serotonin-producing neurons present in the mammalian CNS, a complex long-range projection system provides profuse innervation to the whole brain. Heterogeneity of serotonin receptors, grouped in seven families, and their spatiotemporal expression pattern account for its widespread impact. Although neuronal communication occurs primarily at tiny gaps called synapses, wiring transmission, another mechanism based on extrasynaptic diffusion of neuroactive molecules and referred to as volume transmission, has been described. While wiring transmission is a rapid and specific one-to-one modality of communication, volume transmission is a broader and slower mode in which a single element can simultaneously act on several different targets in a one-to-many mode. Some experimental evidence regarding ultrastructural features, extrasynaptic localization of receptors and transporters, and serotonin-glia interactions collected over the past four decades supports the existence of a serotonergic system of a dual modality of neurotransmission, in which wiring and volume transmission coexist. To date, in spite of the radical difference in the two modalities, limited information is available on the way they are coordinated to mediate the specific activities in which serotonin participates. Understanding how wiring and volume transmission modalities contribute to serotonergic neurotransmission is of utmost relevance for the comprehension of serotonin functions in both physiological and pathological conditions.