Myelin, the multilayered membrane of insulation wrapped around nerve fibers by glial cells (oligodendrocytes), is essential for nervous system function, increasing conduction velocity at least 50-fold. Myelination is essential for brain development. The processes controlling myelination of appropriate axons are not well understood. Myelination begins late in fetal life and continues through childhood and adolescence, but myelination of some brain regions is not completed until the early twenties.
Our research shows that neurotransmitters are released along axons firing action potentials. The neurotransmitters activate receptors on myelinating glia (Schwann cells in the peripheral nervous system and oligodendrocytes in the central nervous system) as well as astrocytes and other cells that, in turn, release growth factors or cytokines that regulate the development of myelinating glia.
In addition to effects of impulse activity on proliferation and differentiation of myelinating glia, we determined that release of the neurotransmitter glutamate from vesicles along axons promotes the initial events in myelin induction. The process involves stimulating the formation of cholesterol-rich signaling domains between oligodendrocytes and axons and increasing the local synthesis of the major protein in the myelin sheath, myelin basic protein, through Fyn kinase–dependent signaling. Such axon-oligodendrocyte signaling would promote myelination of electrically active axons to regulate neural development and function according to environmental experience. The findings are also relevant to demyelinating disorders, such as multiple sclerosis, and to remyelination after axon injury.
The release of neuronal messengers outside synapses has broad biological implications, particularly with regard to communication between axons and glia. We identified a mechanism for nonsynaptic, nonvesicular release of ATP from axons through volume-activated anion channels (VAACs)—activated by microscopic axon swelling during action potential firing. The studies combine imaging of single photons to measure ATP release in a luciferin/luciferase assay with imaging of intrinsic optical signals and intracellular calcium, time-lapse video, and confocal microscopy. Microscopic axon swelling accompanying electrical depolarization of axons activates the VAACs to release ATP. Such nonvesicular, nonsynaptic communication could mediate various activity-dependent interactions between axons and nervous system cells in normal conditions, development, and disease.
ATP Release Movie
Single-photon imaging was used to detect the release of ATP. ATP was detected by adding the firefly proteins (luciferase and Luciferin) that generate light in the tail of a firefly to cultures of mouse sensory neurons. The reaction that generates light requires ATP, so that when ATP is released from a neuron when it fires electrical impulses, a flash of photons is seen.