Extrasynaptic transmission is a unifying term for a wide variety of cellular processes, in which outside of synaptic terminals transmitter substances activate extrasynaptic receptors. Whereas “synaptic transmission” immediately refers to a process occurring at nerve terminals in which the arrival of a presynaptic impulse evokes exocytosis followed by a postsynaptic response within a millisecond time scale, extrasynaptic transmission has a wide diversity of ultrastructural and therefore mechanistic associated phenomena. In comparison to synaptic, extrasynaptic exocytosis may last for seconds or even minutes, thus expanding the timing of neuronal signaling. Extrasynaptic transmission has now been demonstrated in central and peripheral neurons of vertebrates and invertebrates, and involves many different types of transmitter substances than include low molecular weight transmitters (acetilcholine, GABA, glutamate, ATP, and biogenic amines) and peptides (substance P, vasopressin and others). It may occur when transmitters leak out from the synaptic cleft and activate extrasynaptic receptors in neighboring neurons or glial cells, or when axonal varicosities, dendrites or the somata release transmitters in the absence of postsynaptic counterparts.
The release mechanisms also vary from one neuron type to another and from one neuronal compartment to another. In some cases, clear vesicles are apposed to the resting plasma membrane, as in presynaptic terminals. In other cases, transmitters are packed onto dense core vesicles that rest at a distance from the release sites. In between, there are multiple morphological combinations that point to complementary mechanisms in different compartments of the same neuron and some times, even in the same compartment. For example, serotonergic varicosities may combine clear and dense core vesicles in stereotyped arrays.
This diversity adds complexity to the nervous system and raises many questions that are waiting for answers. Extrasynaptic transmission may be the main source of transmitter molecules causing volume transmission, however this still lacks direct demonstration. From the physiological point of view, one may ask how does the neuronal firing pattern evokes synaptic or extrasynaptic transmitter release or what are the physiological effects of these modes of transmission. From the behavioral point of view it becomes interesting to explore how circuits and therefore behaviors are modulated. Some neurological disfunctions may also be related to deficiencies in extrasynaptic transmission, however, again, direct studies are still lacking. Developmental and evolutionary biologists may also find the topic inspiring.
Extrasynaptic transmission not only expands our view about how the nervous system works, but also requires a change in the way we plan our research. New technological and computational tools are now being applied to analyze intracellular and extracellular transmitter mobilizations or long term changes of neuronal circuits. New definitions and mechanisms may become visible. In the meanwhile, this seems to be a good moment for a first common effort to analyze and discuss extrasynaptic transmission in different systems and from different perspectives.
Extrasynaptic transmission is a unifying term for a wide variety of cellular processes, in which outside of synaptic terminals transmitter substances activate extrasynaptic receptors. Whereas “synaptic transmission” immediately refers to a process occurring at nerve terminals in which the arrival of a presynaptic impulse evokes exocytosis followed by a postsynaptic response within a millisecond time scale, extrasynaptic transmission has a wide diversity of ultrastructural and therefore mechanistic associated phenomena. In comparison to synaptic, extrasynaptic exocytosis may last for seconds or even minutes, thus expanding the timing of neuronal signaling. Extrasynaptic transmission has now been demonstrated in central and peripheral neurons of vertebrates and invertebrates, and involves many different types of transmitter substances than include low molecular weight transmitters (acetilcholine, GABA, glutamate, ATP, and biogenic amines) and peptides (substance P, vasopressin and others). It may occur when transmitters leak out from the synaptic cleft and activate extrasynaptic receptors in neighboring neurons or glial cells, or when axonal varicosities, dendrites or the somata release transmitters in the absence of postsynaptic counterparts.
The release mechanisms also vary from one neuron type to another and from one neuronal compartment to another. In some cases, clear vesicles are apposed to the resting plasma membrane, as in presynaptic terminals. In other cases, transmitters are packed onto dense core vesicles that rest at a distance from the release sites. In between, there are multiple morphological combinations that point to complementary mechanisms in different compartments of the same neuron and some times, even in the same compartment. For example, serotonergic varicosities may combine clear and dense core vesicles in stereotyped arrays.
This diversity adds complexity to the nervous system and raises many questions that are waiting for answers. Extrasynaptic transmission may be the main source of transmitter molecules causing volume transmission, however this still lacks direct demonstration. From the physiological point of view, one may ask how does the neuronal firing pattern evokes synaptic or extrasynaptic transmitter release or what are the physiological effects of these modes of transmission. From the behavioral point of view it becomes interesting to explore how circuits and therefore behaviors are modulated. Some neurological disfunctions may also be related to deficiencies in extrasynaptic transmission, however, again, direct studies are still lacking. Developmental and evolutionary biologists may also find the topic inspiring.
Extrasynaptic transmission not only expands our view about how the nervous system works, but also requires a change in the way we plan our research. New technological and computational tools are now being applied to analyze intracellular and extracellular transmitter mobilizations or long term changes of neuronal circuits. New definitions and mechanisms may become visible. In the meanwhile, this seems to be a good moment for a first common effort to analyze and discuss extrasynaptic transmission in different systems and from different perspectives.
