Regulation of synaptic connectivity by glia

Abstract

The human brain contains more than 100 trillion (10(14)) synaptic connections, which form all of its neural circuits. Neuroscientists have long been interested in how this complex synaptic web is weaved during development and remodelled during learning and disease. Recent studies have uncovered that glial cells are important regulators of synaptic connectivity. These cells are far more active than was previously thought and are powerful controllers of synapse formation, function, plasticity and elimination, both in health and disease. Understanding how signalling between glia and neurons regulates synaptic development will offer new insight into how the nervous system works and provide new targets for the treatment of neurological diseases.

Figure 1. The tri-partite synapse

The processes of astrocytes are intimately associated with synapses. This association is both structural and functional. a, Electron micrograph showing a tripartite synapse in the hippocampus. The astrocyte process (blue) ensheaths the perisynaptic area. The axon of the neuron is shown in green, with the dendritic spine in yellow and the postsynaptic density in red and black. Reproduced, with permission, from ref. . b, Schematic representation of a tripartite synapse. Perisynaptic astrocyte processes contain transporters that take up glutamate (Glu, green circles) that has been released into the synapse and return it to neurons in the form of glutamine (Gln). Glutamate receptors on astrocytes (such as metabotropic glutamate receptors) sense synaptic glutamate release, which in turn induces a rise in Ca²⁺ concentration in the astrocytes. One of the main functions of glia at the synapse is to maintain ion homeostasis, for example regulating extracellular K⁺ concentrations and pH.

Figure 2. Glial regulation of synaptic development

Several studies using the retinal ganglion cell culture system have shown that there are at least three classes of factor secreted by astrocytes. These factors control different aspects of the development of glutamate-mediated synapses. a, One type induces the formation of structurally normal but postsynaptically silent synapses. Thrombospondins are an example of this type of factor. b, Another type facilitates presynaptic activity and increases the probability of neurotransmitter release. Cholesterol functions in this way. c, A third type induces the formation of functional synapses or converts silent synapses into active ones by facilitating the insertion of glutamate receptors into postsynaptic sites. These factors have yet to be identified.

Figure 3. Molecular pathways known to regulate axon pruning and synapse elimination by glia in invertebrates

Two transmembrane proteins, Six-microns-under (SIMU) and Draper, regulate the engulfment and phagocytosis of axosomes by glia in Drosophila. These proteins are homologues and have large extracellular regions with multiple epidermal growth factor (EGF)-like repeats and an EMILIN-like domain. SIMU and Draper function in the same pathway, most probably recognizing synaptic debris by binding to unidentified ‘eat-me’ signals on degenerating axons. SIMU seems to be involved in the initial recognition and uptake steps of engulfment, but it lacks an intracellular signalling domain. By contrast, Draper is capable of intracellular signalling and operates downstream of SIMU. The cytoplasmic adaptor protein CED-6 functions downstream of Draper, mediating the internalization and lysosomal degradation of debris. In addition, Draper triggers cytoskeletal rearrangements and phagocytosis through an interaction with the non-receptor tyrosine kinase SHARK. The kinase SRC42A facilitates the SHARK–Draper interaction by phosphorylating Draper.

Figure 4. Regulation of synapse elimination in the mammalian CNS by the complement cascade

An unidentified secreted signal from immature and reactive astrocytes upregulates expression of the complement component C1q in neurons. It is proposed that C1q binds to weaker synapses and tags them for elimination. This elimination might occur through phagocytosis by microglia, mediated by complement receptors at the surface of microglia. Other complement-cascade components such as C3 are also produced by glia in normal and disease conditions, and another possibility is that synapse elimination is triggered by C1q and C3 not only during development but also during the early stages of neurodegenerative diseases.