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Glial Cells Under Physiologic and Pathologic Conditions

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Glial Cells Under Physiologic and Pathologic Conditions BASIC SCIENCE SEMINARS IN NEUROLOGY SECTION EDITOR: HASSAN M. FATHALLAH-SHAYKH, MD Glial Cells Under Physiologic and Pathologic Conditions Pascal Kurosinski, Dipl Biol; Ju¨rgen Go¨tz, PhD lial cells have long been considered to play roles in the nervous system that are unex- citing compared with those of neurons. They provide neurons with nutrients, guide migrating neurons and their precursors during development, and dispose of the brain’s “waste.” Recent evidence, however, suggests that glial cells play more sophisticated, Gneuronlike roles. They integrate neuronal input, modulate synaptic activity, and process signals re- lated to learning and memory. These findings have significant implications for humans with neuro- degenerative diseases. In addition to activation on nervous system injury and during neuronal de- generation, glial cells also degenerate in several neurodegenerative diseases. Therefore, glial cell loss may contribute to the impairment of learning and memory. Therapeutic approaches to combat hu- man neurodegenerative diseases thus need to restore the function of both neurons and glial cells. Arch Neurol. 2002;59:1524-1528 The importance of neurons for central ner- cells that are found in the peripheral ner- vous system (CNS) function is unques- vous system. In close association with neu- tionable. To assess the potential role of glial rons, astrocytes enwrap synaptic termi- cells, phylogeny may provide a clue. In the nals and make extensive contacts with nematode Caenorhabditis elegans, for ex- endothelial cells from the capillaries. More- ample, a total of 302 neurons but only 56 over, astrocytes are interconnected with glial and supporting cells have been iden- one another by gap junctions. In the den- tified. As one rises through phylogeny, the tate gyrus of the hippocampus, they give ratio of glia to neurons increases, and in rise to new neurons throughout life in humans, the brain contains the highest ra- many vertebrates, including humans.1 tio of glia to neurons (at least 10:1). Con- Historically, glial cells were assigned sequently, one is tempted to suggest that several functions in supporting neurons glial cells play important roles in higher during development and throughout life. cognitive functions. Glial control of the survival of associated Glial and neuronal cells arise from neurons is dependent on prior neuronal progenitors that are initially multipotent triggering of glial cell fate commitment and but gradually become restricted to the neu- trophic factor expression. In addition, glial ronal or glial lineage. Differentiation oc- cells control the migration of neurons dur- curs in a stereotyped sequence whereby ing development. Embryonic neurons are neurons are generated first, followed by typically born at some distance from their glial cells, which differentiate after neu- final sites in the mature nervous system. rogenesis is largely completed. Glial cells The pathways taken by newborn neurons of the CNS can be divided into microglia are specific and depend on cellular con- and macroglia. Microglia are macrophage- tacts and diffusible guidance cues, most of like cells that serve a phagocytic func- which are provided by glial cells and their tion. Macroglia are composed of astro- precursors. Development and lamination cytes and oligodendrocytes, which are the of the mammalian neocortex is con- CNS equivalent of myelinating Schwann trolled by a set of specialized neuroepi- thelial radial glial cells that provide the mi- From the Division of Psychiatry Research, University of Zurich, Zurich, Switzerland. gration scaffold used by roughly 90% of (REPRINTED) ARCH NEUROL / VOL 59, OCT 2002 WWW.ARCHNEUROL.COM 1524 ©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 cortical neurons. Several lines of evi- receptors coupled to intracellular cal- ROLE IN MEMORY dence indicate that these radial glia cium mobilization, neuronal activ- AND LEARNING are the precursors of astrocytes in the ity may regulate astrocytic calcium mature brain. An analogous pro- levels.4 Indeed, several laboratories What is the role of glial cells in cess occurs during the migration of have demonstrated that astrocytes memory and learning? Studies in newborn neuronal granule cells in and perisynaptic Schwann cells re- brain slices showed that activation of the cerebellum along Bergmann glial spond to synaptic activity through the astrocytes increased miniature in- processes from the internal granule activation of glial receptors.3 hibitory postsynaptic currents in hip- cell layer of the developing postna- In addition to integration of pocampal pyramidal neurons. Astro- tal cerebellum. neurotransmitter input, astrocytes re- cytes may therefore be necessary in lease their own transmitters that act the activity-dependent modulation of NEURONAL PROPERTIES on neighboring neurons and modu- inhibitory synapses in the hippocam- OF GLIAL CELLS late their function, suggesting a bi- pus.6 A role of astrocytes in synaptic directional signaling pathway be- function is also supported by results Additional, more elaborate func- tween astrocytes and neurons (Figure of studies in mice lacking the inter- tions were recently assigned to glial 1). If glial cells can release neuro- mediate-filament glial fibrillary acidic cells. In the mature nervous sys- transmitters in a regulated manner, protein (GFAP), a protein found pre- tem, examination at the ultrastruc- this process must be a fundamental dominantly in astrocytes of the CNS. tural level reveals a tripartite struc- component of their dialogue with Although astrocytes were present in ture involving the astrocyte that can neurons during synaptic activity. the CNS of the mutant mice, they con- be intimately associated with the A compartmentalization remi- tained a severely reduced number of synapse and that literally enwraps niscent of that of neurons has been intermediate filaments. Since astro- many presynaptic and postsynap- demonstrated for the cerebellar Berg- cytic processes contact synapses and tic terminals2 (Figure 1). This close mann glia. These highly ramified may modulate synaptic function, physical relationship probably pro- glial cells consist of hundreds of in- McCall et al7 examined whether the vides an opportunity for many func- dependent compartments, called mi- hippocampal CA1 region of GFAP- tional interactions between astro- crodomains, that are capable of au- deficient mice was altered in long- cytes and neurons. As an astrocyte tonomous interactions with the term potentiation (the increase in syn- can make contacts with a neuron and particular group of synapses they en- aptic potential after brief high- a capillary, it has the potential to wrap. Stimulation of adjacent par- frequency trains of stimulation). The shuffle nutrients and metabolites be- allel fibers induces localized eleva- mutant mice indeed displayed en- tween the blood supply and the ac- tions of intracellular calcium levels hanced long-term potentiation com- tive neuron (Figure 1). Further- in the Bergmann glia.5 pared with control mice. Therefore, more, as a single astrocyte can make contacts with multiple neurons, Capillary these nonneuronal cells are posi- Glia-Glia Signaling tioned to provide information trans- Through Gap Junction Nutrients fer between neighboring neurons. In the stratum radiatum hippo- campi, for example, about 50% of the synapses have astrocytic processes, Transmitter and in 30% of the synapses, an astro- Receptor cyte process separates 2 neighboring Astrocyte synapses (Figure 1). In addition, as- trocytes almost exclusively sur- round synapses that have a high prob- ability of neurotransmitter release. Nutrients Astrocytes express functional receptors for many different neuro- transmitters. Binding to these recep- tors leads to changes in intracellular calcium levels and even to oscilla- tions in internal calcium levels. Many of the initial studies that demon- strate calcium excitability of astro- Neuron cytes were performed in cell cul- Figure 1. Glial cells under physiologic conditions in the adult brain. Astrocytes make contacts with ture, but studies using acutely neurons and capillaries and shuffle nutrients between the blood supply and the active neuron. As a single isolated brain slices and later acutely astrocyte can make contacts with multiple neurons, these nonneuronal cells are positioned to transfer isolated hippocampi have sup- information between neighboring neurons. Examination at the ultrastructural level (inset) reveals a ported the calcium excitability prop- tripartite structure involving the astrocyte that can be intimately associated with the synapse and enwraps many presynaptic and postsynaptic terminals. Astrocytes integrate neurotransmitter inputs and release erty of astrocytes. As astrocytes pos- their own transmitters that act on neighboring neurons. Astrocytes communicate with each other using sess a number of neurotransmitter gap junctions and neurotransmitter-mediated signaling. Adapted in part from Haydon.3 (REPRINTED) ARCH NEUROL / VOL 59, OCT 2002 WWW.ARCHNEUROL.COM 1525 ©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Alzheimer Disease Tauopathies cells outnumbered immunoreac- A B tive neurons.12 The glial abnormali- ties of corticobasal degeneration Amyloid Plaque Disrupted Disrupted Neuro-Glia Glia-Glia include astrocytic plaques and nu- Signaling Signaling Cytotoxicity merous tau-immunoreactive inclu- sions in the white
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