New insights into neuron-glia communication

Abstract

Two-way communication between neurons and nonneural cells called glia is essential for axonal conduction, synaptic transmission, and information processing and thus is required for normal functioning of the nervous system during development and throughout adult life. The signals between neurons and glia include ion fluxes, neurotransmitters, cell adhesion molecules, and specialized signaling molecules released from synaptic and nonsynaptic regions of the neuron. In contrast to the serial flow of information along chains of neurons, glia communicate with other glial cells through intracellular waves of calcium and via intercellular diffusion of chemical messengers. By releasing neurotransmitters and other extracellular signaling molecules, glia can affect neuronal excitability and synaptic transmission and perhaps coordinate activity across networks of neurons.

Fig. 1

Major types of glial cells in the nervous system. (A) An electron micrograph of a mouse sensory axon in the process of becoming myelinated by a Schwann cell. Note the multiple layers of dark myelin membrane that the Schwann cell is wrapping around the nerve axon to insulate it for rapid long-distance conduction of neural impulses. (B) Astrocytes do not form myelin, but they form networks of communicating cells within the CNS, and they interact with neurons to support and modulate many of their functions. (C) Olidgodendrocytes form myelin around CNS axons with multiple cellular extensions from the cell body. (D) Schwann cells form myelin around PNS axons and ensheath multiple small unmyelinated axons into bundles. (E) Microglia enter the CNS early in development from embryonic cells of nonectodermal origin and they respond to brain injury and disease. These cells were grown in cell culture and labeled by fluorescence immunocytochemistry for specific proteins expressed by each cell type (GFAP, O4, S100, OX-42, in B to E, respectively). Scale bars, 100 nm (A), 25 μm (B, C).

Fig. 2

Calcium imaging reveals communication between neurons and glia. (A) Molecules released during synaptic transmission bind receptors on glia that cause increases in intracellular Ca²⁺ (rainbow colored cells), which are propagated as waves through glial networks. (B) Increases or decreases in axonal firing may coincide with the passage of a glial Ca²⁺ wave. Oligodendrocytes (purple) myelinate CNS axons. v_m, membrane voltage.

Fig. 3

Synaptic astrocytes (yellow) regulate synaptic transmission by responding to signaling molecules, such as ATP and glutamate, released from the presynaptic neuron during synaptic transmission. Astrocytes communicate with adjacent astrocytes via gap junctions (GJ) and with distant astrocytes via extracellular ATP. The rise in Ca²⁺ causes release of glutamate from astrocytes, and ATP is released via an unknown mechanism, which propagates ATP signaling to adjacent cells. Astrocytes may also regulate synaptic transmission by uptake of glutamate from the synaptic cleft via membrane transporters (green arrow) or the release of glutamate upon reversal of the transporter induced by elevated intracellular Na⁺ (red arrow). Other substances, such as d-serine, strengthen synaptic transmission by coactivating NMDA receptors in the postsynaptic membrane, or reduce synaptic transmission by secreting transmitter-binding proteins ( TBP). (Inset) An electron micrograph of a synapse surrounded by an astrocyte (yellow) from the spinal cord of rat (Courtesy of M. H. Ellisman, National Center for Microscopy and Imaging Research, University of California, San Diego). GluR, glutamate receptor; Ado, adenosine; IP3, inositol trisphosphate; P1, adenosine receptor; P2, ATP receptor.

Fig. 4

Nodal glia play an important role in the formation, organization, and maintenance of myelinated axons. (A) An electron micrograph of a longitudinal section through the Node of Ranvier in the spinal dorsal root of rat, showing the intricate association between myelinating glia and axons (courtesy of M. H. Ellisman, National Center for Microscopy and Imaging Research, University of California, San Diego). (B) Three specific domains are defined by axon-glial interactions at the node of Ranvier: the Na⁺ channel-enriched node of Ranvier, the adjacent paranode (PN), the juxtaparanodal region (JP), which contains delayed rectifier K⁺ channels, and the internode (IN). This axon domain organization is regulated by soluble signals from myelinating glia as well as direct contact and interactions between proteins expressed on the surface of axons and glia. At the paranode, the transmembrane protein Caspr is found on the axon surface in association with the GPI anchored cell adhesion molecule, contactin (Cont). This molecular complex interacts with the glial cell adhesion molecule, neurofascin 155 (NF) and anchors the intercellular junction to the axonal cytoskeleton through the actin associated protein 4.1B, which binds to the cytoplasmic domain of Caspr. (*) Demyelination can lead to axon degeneration, indicating the necessity of continual communication between the axon and myelinating glia for maintaining axonal integrity (87, 95). KCh, K⁺ channel, NaCh, Na⁺ channel.