Neurotransmitter Release from Neurons & Astrocytes

Neurotransmitter Release from Neurons

The nervous system is built by two cellular circuits represented by a synoptically connected neuronal network and a complex web of glial cells. Neurons communicate via rapidly propagating electrical signals, the action potentials generated by their excitable plasmalemma. First, action potentials are converted into chemical signals; this process is accomplished through Ca²⁺-dependent vesicular release of neurotransmitters from the presynaptic terminal. Next, this chemical signal carried by neurotransmitters is converted into either electrical excitation or metabolic cytoplasmic signals on the postsynaptic level, thus realizing information transfer in neuronal networks. Finally, in neurons, the calcium-dependent release of neurotransmitters is caused by the exocytosis of quanta of neurotransmitter-filled vesicles from the nerve terminal.

Neurotransmitter Release from Astrocytes

Although unable to generate plasmalemmal action potentials, glial cells communicate through intracellular routes or directly communicate through gap junctions, integrating glia into the three-dimensional web. At the same time, glial cells are endowed with a full complement of membrane channels and neurotransmitter receptors; further, glia can release neurotransmitters via several regulated pathways, including exocytosis. These mechanisms are central for integration within neuronal-glial circuits. Astroglia cells, the most numerous glial cells, can express all types of neurotransmitter receptors known so far. These receptors are activated by released neurotransmitters or by molecules diffusing in the brain extracellular space (volume transmitters). As a result, the astroglia syncytium controls and influences neuronal networks, being responsible for as yet unknown but certainly a quite important part of integrative processes in the central nervous system (CNS).

One of the vital functions of astrocytes in the CNS is to regulate neurotransmitter concentrations in the extracellular space. Astrocytes possess various molecular mechanisms that allow fast and local changes of Na⁺, including neurotransmitter receptors and NeuTs. Most NeuTs utilize transmembrane Na⁺ gradient for the regulation of neurotransmitter levels in the extracellular space. Local intracellular Na⁺ transients occurring in astrocytes, for example, via the activation of ionotropic neurotransmitter receptors, can affect the driving force for neurotransmitter uptake, in turn modulating the Spatio-temporal profiles of neurotransmitter levels in the extracellular space. Through this mechanism, these astrocytic Na1 signals will profoundly impact neuronal communication throughout the central nervous system.

Glutamate Releases from Astrocytes

With the recent demonstration of vesicular glutamate transporters and their physiological and homeostatic role, glutamate has all the hallmarks of a conventional neurotransmitter. After glutamate and GABA have been released from neurons as transmitters, some transmitter is partly reaccumulated into neurons or otherwise replenished to maintain adequate levels of excitatory neurotransmission. Nevertheless, most released glutamate is probably accumulated by powerful virtually exclusively astrocytic transporters and thus returned to astrocytes. Here a part is oxidized, whereas the remaining is again converted to glutamine and returned to neurons through the glutamine-glutamate/ GABA cycle for reuse as the transmitter. Glutamine is released from astrocytes via gap junction hemichannels under certain conditions. The astrocytic glutamine release mechanism is a central process in the synapses’ ability to maintain a sustained neurotransmission level.

• Mechanisms of Glutamate Releases from Astrocytes

Three prominent mechanisms have been suggested as potential pathways to underlie glutamate release from astrocytes: reverse operation of glutamate transporters, swelling-induced release, and calcium-dependent exocytosis. Under depolarization conditions or when the Na⁺/K⁺ electrochemical gradient used by these transporters has been reversed, glutamate can be released through these transporters. However, this does not underlie calcium-dependent glutamate release because ligands that cause glutamate release do not depolarize astrocytes, and transport inhibitors do not attenuate the magnitude of ligand-induced glutamate release. In conclusion, both glutamate and GABA operate in neuronal-astrocytic networks, providing excitation and inhibition, respectively. On the one hand, both amino acid transmitters are bona fide neurotransmitters; on the other hand, their importance for regulating brain activity and how they can exert their regulatory activity reaches far beyond conventional transmitters.

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