Extrasynaptic Communication

Abstract

Streams of action potentials or long depolarizations evoke a massive exocytosis of transmitters and peptides from the surface of dendrites, axons and cell bodies of different neuron types. Such mode of exocytosis is known as extrasynaptic for occurring without utilization of synaptic structures. Most transmitters and all peptides can be released extrasynaptically. Neurons may discharge their contents with relative independence from the axon, soma and dendrites. Extrasynaptic exocytosis takes fractions of a second in varicosities or minutes in the soma or dendrites, but its effects last from seconds to hours. Unlike synaptic exocytosis, which is well localized, extrasynaptic exocytosis is diffuse and affects neuronal circuits, glia and blood vessels. Molecules that are liberated may reach extrasynaptic receptors microns away. The coupling between excitation and exocytosis follows a multistep mechanism, different from that at synapses, but similar to that for the release of hormones. The steps from excitation to exocytosis have been studied step by step for the vital transmitter serotonin in leech Retzius neurons. The events leading to serotonin exocytosis occur similarly for the release of other transmitters and peptides in central and peripheral neurons. Extrasynaptic exocytosis occurs commonly onto glial cells, which react by releasing the same or other transmitters. In the last section, we discuss how illumination of the retina evokes extrasynaptic release of dopamine and ATP. Dopamine contributes to light-adaptation; ATP activates glia, which mediates an increase in blood flow and oxygenation. A proper understanding of the workings of the nervous system requires the understanding of extrasynaptic communication.

Keywords: extrasynaptic release; glia; modulation; nerve cell communication; serotonin; somatic exocytosis.

Figure 1

Schematic representation of the mechanism for somatic exocytosis of serotonin in Retzius neurons. (A) Electrical activity sets in motion the transport of dense core vesicles (dcv) to the plasma membrane. In response to a train of action potentials, L-type calcium channels (LCach) open. Calcium entry activates ryanodine receptors (RyR) in the endoplasmic reticulum (er) and produces calcium-induced calcium release. The amplified calcium wave invades the soma; in the mitochondria (mit), calcium stimulates the synthesis of ATP, which activates kinesin motors (km) and vesicle transport along microtubules (mt). (B) Vesicles enter the actin cortex and myosin motors (MyM) carried by the vesicles couple to actin filaments and contribute to the transport. Release is maintained by a positive feedback loop in which the serotonin that is released activates 5-HT2 receptors (5-HT2R). Activation of phospholipase C (PLC) produces IP₃ which acts on its receptors (IP₃R) to activate calcium release. Such calcium maintains exocytosis going on until the last vesicles fuse (Adapted from Leon-Pinzon et al., 2014).

Figure 2

Synaptic and perisynaptic exocytosis. (A) Low frequency stimulation activates presynaptic P or N type calcium channels and evokes fusion of synaptic vesicles in the active zone. Transmitter liberated into the synaptic cleft activates post-synaptic receptors. (B) Increasing the stimulation frequency increases synaptic exocytosis and produces transmitter spillover, which acts on extrasynaptic receptors in adjacent glia and neuronal processes. (C) In the presence of perisynaptic dense-core vesicles, a low stimulation frequency evokes mostly synaptic release. (D) Increasing the stimulation frequency produces summation of calcium currents flowing through L type channels. Dense core vesicles are transported to the plasma membrane and fuse in presynaptic regions of the terminal. Transmitter that has been released acts on extrasynaptic receptors in the pre-and post-synaptic terminals, and also in adjacent glial and neuronal processes. Clear and dense core vesicles may have the same or different transmitters. Dense core vesicles also may contain peptides.