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• W1609916908 abstract "The nervous system consists of neurons and glial cells. Neurons generate and propagate electrical and chemical signals, whereas glia function mainly to modulate neuron function and signaling. Just as there are many different kinds of neurons with different roles, there are also many types of glia that perform diverse functions. For example, glia make myelin; modulate synapse formation, function, and elimination; regulate blood flow and metabolism; and maintain ionic and water homeostasis to name only a few. Although proteomic approaches have been used extensively to understand neurons, the same cannot be said for glia. Importantly, like neurons, glial cells have unique protein compositions that reflect their diverse functions, and these compositions can change depending on activity or disease. Here, I discuss the major classes and functions of glial cells in the central and peripheral nervous systems. I describe proteomic approaches that have been used to investigate glial cell function and composition and the experimental limitations faced by investigators working with glia. The nervous system consists of neurons and glial cells. Neurons generate and propagate electrical and chemical signals, whereas glia function mainly to modulate neuron function and signaling. Just as there are many different kinds of neurons with different roles, there are also many types of glia that perform diverse functions. For example, glia make myelin; modulate synapse formation, function, and elimination; regulate blood flow and metabolism; and maintain ionic and water homeostasis to name only a few. Although proteomic approaches have been used extensively to understand neurons, the same cannot be said for glia. Importantly, like neurons, glial cells have unique protein compositions that reflect their diverse functions, and these compositions can change depending on activity or disease. Here, I discuss the major classes and functions of glial cells in the central and peripheral nervous systems. I describe proteomic approaches that have been used to investigate glial cell function and composition and the experimental limitations faced by investigators working with glia. The nervous system is composed of neurons and glial cells that function together to create complex behaviors. Traditionally, glia have been considered to be merely passive contributors to brain function, resulting in a pronounced neurocentric bias among neuroscientists. Some of this bias reflects a paucity of knowledge and tools available to study glia. However, this view is rapidly changing as new tools, model systems (culture and genetic), and technologies have permitted investigators to show that glia actively sculpt and modulate neuronal properties and functions in many ways. Glia have been thought to outnumber neurons by 10:1, although more recent studies suggest the ratio in the human brain is closer to 1:1 with region-specific differences (1.Azevedo F.A. Carvalho L.R. Grinberg L.T. Farfel J.M. Ferretti R.E. Leite R.E. Jacob Filho W. Lent R. Herculano-Houzel S. Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain.J. Comp. Neurol. 2009; 513: 532-541Crossref PubMed Scopus (1206) Google Scholar). There are many different types of glia, some of which are specific to the central nervous system (CNS), 1The abbreviations used are:CNScentral nervous systemPNSperipheral nervous system. whereas others are found only in the peripheral nervous system (PNS). The main types of CNS glia include astrocytes, oligodendrocytes, ependymal cells, radial glia, and microglia. In the PNS, the main glial cells are Schwann cells, satellite cells, and enteric glia. These cells differ and are classified according to their morphologies, distinct anatomical locations in the nervous system, functions, developmental origins, and unique molecular compositions. Among the different classes of glia there are additional subclasses that reflect further degrees of specialization. In this review, I will discuss the characteristics and functions of the major glial cell types including astrocytes, microglia, and the myelin-forming oligodendrocytes (CNS) and Schwann cells (PNS). Because of space limitations, it is impossible to give a complete accounting of all glia and what is known about each of these cell types. Therefore, I encourage the interested reader to refer to some of the many excellent reviews referenced below that focus on individual glial cell types. Finally, I will discuss proteomic studies of glial cell function and some of the unique challenges investigators face when working with these cells. central nervous system peripheral nervous system. Astrocytes and neurons are derived from a common neuroepithelial precursor. These precursors undergo a gliogenic switch that depends on unique transcription factors regulated by both spatial and temporal elements. It has even been suggested that the spatial and temporal regulation of astrocyte development results in astrocyte heterogeneity, which in turn contributes to overall brain patterning (2.Rowitch D.H. Kriegstein A.R. Developmental genetics of vertebrate glial-cell specification.Nature. 2010; 468: 214-222Crossref PubMed Scopus (447) Google Scholar). Astrocytes are the most numerous glial cell type in the central nervous system. In the cortex, most astrocytes are highly ramified with very fine processes that together define the domain of an individual astrocyte. In the healthy brain, adjacent astrocytes do not overlap, resulting in a “tiled” brain structure defined by astrocyte territory (3.Bushong E.A. Martone M.E. Jones Y.Z. Ellisman M.H. Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains.J. Neurosci. 2002; 22: 183-192Crossref PubMed Google Scholar). Astrocytes are commonly identified in immunohistological experiments using antibodies against glial fibrillary acidic protein (Fig. 1A). More recently, methodologies for genetically labeling astrocytes using astrocyte-specific drivers (e.g. glial fibrillary acidic protein and Aldh1L1) have become available (4.Tsai H.H. Li H. Fuentealba L.C. Molofsky A.V. Taveira-Marques R. Zhuang H. Tenney A. Murnen A.T. Fancy S.P. Merkle F. Kessaris N. Alvarez-Buylla A. Richardson W.D. Rowitch D.H. Regional astrocyte allocation regulates CNS synaptogenesis and repair.Science. 2012; 337: 358-362Crossref PubMed Scopus (349) Google Scholar, 5.Kim J.G. Suyama S. Koch M. Jin S. Argente-Arizon P. Argente J. Liu Z.W. Zimmer M.R. Jeong J.K. Szigeti-Buck K. Gao Y. Garcia-Caceres C. Yi C.X. Salmaso N. Vaccarino F.M. Chowen J. Diano S. Dietrich M.O. Tschöp M.H. Horvath T.L. Leptin signaling in astrocytes regulates hypothalamic neuronal circuits and feeding.Nat. Neurosci. 2014; 17: 908-910Crossref PubMed Scopus (225) Google Scholar) and have provided new insights into astrocyte development, structure, and function. These tools may also prove to be extremely useful in the application of proteomic approaches to understanding astrocyte function. The very fine processes of astrocytes form subcellular specializations that surround or contact neurons, especially at synapses, or endfeet that contact vasculature. Current estimates suggest that each astrocyte associates with about four neurons, 105 synapses, and one to two capillaries (6.Halassa M.M. Fellin T. Takano H. Dong J.H. Haydon P.G. Synaptic islands defined by the territory of a single astrocyte.J. Neurosci. 2007; 27: 6473-6477Crossref PubMed Scopus (509) Google Scholar). Astrocytes are essential elements of neural circuits because they are responsible for regulation of local blood flow as part of the neurovascular unit. Neuronal activity, reflected in the release of neurotransmitters from neurons, activates receptors on astrocytes. This in turn triggers a Ca2+ response that is thought to promote release of vasoactive substances in the astrocytic endfeet that contact blood vessels (7.Filosa J.A. Morrison H.W. Iddings J.A. Du W. Kim K.J. Beyond neurovascular coupling, role of astrocytes in the regulation of vascular tone.Neuroscience. 2015; (10.1016/j.neuroscience.2015.03.064)Google Scholar, 8.MacVicar B.A. Newman E.A. Astrocyte regulation of blood flow in the brain.Cold Spring Harb. Perspect. Biol. 2015; 7: a020388Crossref PubMed Scopus (177) Google Scholar). Astrocytes are proposed to not only promote increased blood flow and local oxygenation but also to take up glucose from the blood, convert it to lactate, and then release it to neurons for local energy use (9.Magistretti P.J. Neuron-glia metabolic coupling and plasticity.J. Exp. Biol. 2006; 209: 2304-2311Crossref PubMed Scopus (532) Google Scholar). Thus, astrocytes couple the demands of neuronal activity and metabolism to local blood flow. Neuronal activity increases extracellular K+; if uncontrolled during high levels of activity, this can depolarize neuronal membrane potentials to pathological states. Astrocytes buffer extracellular K+ concentrations through Kir4.1 inwardly rectifying K+ channels (10.Butt A.M. Kalsi A. Inwardly rectifying potassium channels (Kir) in central nervous system glia: a special role for Kir4.1 in glial functions.J. Cell. Mol. Med. 2006; 10: 33-44Crossref PubMed Scopus (228) Google Scholar). These channels take up excess K+ by passive diffusion down the K+ electrochemical potential gradient. Oligodendrocytes also express Kir4.1, and loss of Kir4.1 from both astrocytes and oligodendrocytes results in profound vacuolization of myelin, neuronal death, and premature lethality (11.Neusch C. Papadopoulos N. Müller M. Maletzki I. Winter S.M. Hirrlinger J. Handschuh M. Bähr M. Richter D.W. Kirchhoff F. Hülsmann S. Lack of the Kir4.1 channel subunit abolishes K+ buffering properties of astrocytes in the ventral respiratory group: impact on extracellular K+ regulation.J. Neurophysiol. 2006; 95: 1843-1852Crossref PubMed Scopus (148) Google Scholar, 12.Neusch C. Rozengurt N. Jacobs R.E. Lester H.A. Kofuji P. Kir4.1 potassium channel subunit is crucial for oligodendrocyte development and in vivo myelination.J. Neurosci. 2001; 21: 5429-5438Crossref PubMed Google Scholar). Astrocytes also regulate activity-dependent volume changes of the extracellular space by controlling water homeostasis through the aquaporin-4 water channel (13.Nagelhus E.A. Mathiisen T.M. Ottersen O.P. Aquaporin-4 in the central nervous system: cellular and subcellular distribution and coexpression with KIR4.1.Neuroscience. 2004; 129: 905-913Crossref PubMed Scopus (413) Google Scholar). These same water channels are the primary target of autoantibodies in neuromyelitis optica, an autoimmune astrocytopathy resulting in profound demyelination in the CNS. Thus, astrocytes play essential roles in controlling neuronal excitability and brain homeostasis by regulating brain volume and K+ concentrations. The main computational unit of the brain is the synapse. The discovery that astrocytes participate in many aspects of synapse function including their development, refinement, and modulation of activity has helped to firmly establish the view that astrocytes are not simply passive regulators of brain homeostasis but in fact are major contributors to cognition, learning, and memory. Some of the earliest studies on the role of astrocytes in synapse formation used highly purified cultures of retinal ganglion cells to show that the addition of astrocyte-conditioned medium induces the development of large numbers of synapses (14.Ullian E.M. Sapperstein S.K. Christopherson K.S. Barres B.A. Control of synapse number by glia.Science. 2001; 291: 657-661Crossref PubMed Scopus (1058) Google Scholar). These experiments supported the conclusion that astrocytes secrete factors that promote synaptogenesis and synapse function. This observation led to extensive searches for these factors, which are now known to contribute to structural assembly of synapses and modulation of pre- and postsynaptic function (15.Chung W.S. Allen N.J. Eroglu C. Astrocytes control synapse formation, function, and elimination.Cold Spring Harb. Perspect. Biol. 2015; 7: a020370Crossref PubMed Scopus (405) Google Scholar). For example, thrombospondins, which are large extracellular matrix molecules secreted by astrocytes, have a myriad of functions including the induction of glutamatergic synapse formation (16.Christopherson K.S. Ullian E.M. Stokes C.C. Mullowney C.E. Hell J.W. Agah A. Lawler J. Mosher D.F. Bornstein P. Barres B.A. Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis.Cell. 2005; 120: 421-433Abstract Full Text Full Text PDF PubMed Scopus (1181) Google Scholar) and the inhibition of presynaptic release (17.Crawford D.C. Jiang X. Taylor A. Mennerick S. Astrocyte-derived thrombospondins mediate the development of hippocampal presynaptic plasticity in vitro.J. Neurosci. 2012; 32: 13100-13110Crossref PubMed Scopus (46) Google Scholar). Not only do astrocytes promote synapse assembly, but recent studies of astrocyte gene expression suggested that they also participate in the refinement of neural circuits during development and in adult animals by activity-dependent synapse elimination. Specifically, astrocytes utilize MEGF10 and MERTK phagocytic pathways to promote synapse engulfment. Loss of these pathways results in failure to properly refine visual circuits and a greater number of weak synapses (18.Chung W.S. Clarke L.E. Wang G.X. Stafford B.K. Sher A. Chakraborty C. Joung J. Foo L.C. Thompson A. Chen C. Smith S.J. Barres B.A. Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways.Nature. 2013; 504: 394-400Crossref PubMed Scopus (720) Google Scholar). The close physical apposition of astrocytes to synapses suggested that astrocytes may directly participate in neurotransmission. Indeed, this close apposition has led to the idea of the so-called tripartite synapse where astrocytes affect synapse function (19.Haydon P.G. Carmignoto G. Astrocyte control of synaptic transmission and neurovascular coupling.Physiol. Rev. 2006; 86: 1009-1031Crossref PubMed Scopus (1001) Google Scholar). Many different laboratories have shown that astrocytes express neurotransmitter receptors, and the release of neurotransmitter can bidirectionally regulate astrocyte and neuron function (20.Martín R. Bajo-Grañeras R. Moratalla R. Perea G. Araque A. Circuit-specific signaling in astrocyte-neuron networks in basal ganglia pathways.Science. 2015; 349: 730-734Crossref PubMed Scopus (193) Google Scholar). Astrocytes remove excess extracellular glutamate through excitatory amino acid transporters. Conversely, astrocytes can also release neurotransmitter to directly modify synapse properties. However, the concept of gliotransmission remains very controversial because one recent study claimed that the transgenic mouse (expressing a dominant-negative domain of the vesicular SNARE protein) originally used to discover gliotransmission was not specific to astrocytes (21.Fujita T. Chen M.J. Li B. Smith N.A. Peng W. Sun W. Toner M.J. Kress B.T. Wang L. Benraiss A. Takano T. Wang S. Nedergaard M. Neuronal transgene expression in dominant-negative SNARE mice.J. Neurosci. 2014; 34: 16594-16604Crossref PubMed Scopus (115) Google Scholar). Astrocytes are prominent contributors not only to normal brain function but also play key roles in the brain's reaction to disease or injury. The response of astrocytes to injury or disease is called astrogliosis and may be defined by context-dependent morphological and molecular changes (22.Burda J.E. Sofroniew M.V. Reactive gliosis and the multicellular response to CNS damage and disease.Neuron. 2014; 81: 229-248Abstract Full Text Full Text PDF PubMed Scopus (873) Google Scholar). Astrogliosis is a prominent feature of many diseases and injuries including Alzheimer disease, stroke, epilepsy, and traumatic brain and spinal cord injury (23.Birch A.M. Katsouri L. Sastre M. Modulation of inflammation in transgenic models of Alzheimer's disease.J. Neuroinflammation. 2014; 11: 25Crossref PubMed Scopus (92) Google Scholar, 24.Gleichman A.J. Carmichael S.T. Astrocytic therapies for neuronal repair in stroke.Neurosci. Lett. 2014; 565: 47-52Crossref PubMed Scopus (62) Google Scholar, 25.Devinsky O. Vezzani A. Najjar S. De Lanerolle N.C. Rogawski M.A. Glia and epilepsy: excitability and inflammation.Trends Neurosci. 2013; 36: 174-184Abstract Full Text Full Text PDF PubMed Scopus (515) Google Scholar). In response to a severe injury such as a spinal cord or traumatic brain injury, astrocytes become reactive and undergo a plethora of changes including cytoskeletal hypertrophy characterized by increased expression of glial fibrillary acidic protein and proliferation, and astrocytes begin to express many extracellular matrix molecules including chondroitin sulfate proteoglycans, laminins, and fibronectin (26.Yuan Y.M. He C. The glial scar in spinal cord injury and repair.Neurosci. Bull. 2013; 29: 421-435Crossref PubMed Scopus (141) Google Scholar). Together, these reactive astrocytes and the extracellular matrix form a dense glial scar that has both positive and negative consequences for nervous system repair. On the positive side, the glial scar promotes repair by limiting tissue damage due to inflammation (27.Sofroniew M.V. Astrocyte barriers to neurotoxic inflammation.Nat. Rev. Neurosci. 2015; 16: 249-263Crossref PubMed Scopus (686) Google Scholar); on the negative side, the extracellular matrix molecules comprising the glial scar are potent inhibitors of axon regeneration (28.Sharma K. Selzer M.E. Li S. Scar-mediated inhibition and CSPG receptors in the CNS.Exp. Neurol. 2012; 237: 370-378Crossref PubMed Scopus (144) Google Scholar). Future studies will be required to separate the beneficial effects of astrogliosis from the detrimental effects of the glial scar on neural repair and regeneration. Malignant glioma can also result from the transformation of astrocytes into astrocytomas (29.Zong H. Parada L.F. Baker S.J. Cell of origin for malignant gliomas and its implication in therapeutic development.Cold Spring Harb. Perspect. Biol. 2015; 7: a020610Crossref PubMed Scopus (104) Google Scholar). Treatment of these cancers is especially difficult because of their resistance to chemotherapy and their highly invasive nature. Current efforts focus on defining the genetic changes in astrocytes that lead to transformation and the resulting phenotypic consequences of the mutations. Myelin is a key evolutionary adaptation unique to vertebrates that permitted the development of a complex nervous system. Myelin wraps axons as a multilamellar membrane sheath made by oligodendrocytes in the CNS and Schwann cells in the PNS (Fig. 1B). In the CNS, a single oligodendrocyte may contact and myelinate many axons, but in the PNS, a single Schwann cell myelinates only one axon. Thus, in the PNS, a myelinated axon consists of one axon ensheathed by many Schwann cells lined up one after another like very long beads on a string. During development, both oligodendrocytes and Schwann cells follow a well defined differentiation program that depends on distinct transcription factors and interactions with environmental cues (30.Jessen K.R. Mirsky R. The origin and development of glial cells in peripheral nerves.Nat. Rev. Neurosci. 2005; 6: 671-682Crossref PubMed Scopus (981) Google Scholar, 31.Gallo V. Deneen B. Glial development: the crossroads of regeneration and repair in the CNS.Neuron. 2014; 83: 283-308Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar). In the brain and spinal cord, oligodendrocytes arise from precursors found in the subventricular zone and the ventral neural tube, respectively. In contrast, Schwann cells are neural crest derivatives. The myelin sheath confers several important properties on axons that profoundly influence axon physiology: myelin reduces axonal membrane capacitance while simultaneously increasing the resistance to ion flux across the plasma membrane. This results in a decrease in the time constant and increase in length constant. In addition to these passive electrical properties, myelinating oligodendrocytes and Schwann cells also actively recruit and cluster ion channels (Na+ and K+ channels) at regularly spaced gaps in the myelin sheath called nodes of Ranvier (Fig. 1C). Clustering of ion channels restricts transmembrane ionic currents to the nodes. Together, the decrease in capacitance, increase in transverse membrane resistance, and clustering of ion channels dramatically increase the conduction velocity of axonal action potentials. The increase in conduction velocity means that axons can be smaller, resulting in dramatic space savings, which in turn allows for a more complex and interconnected nervous system. Finally, the decrease in axon diameter and restriction of transmembrane currents to the nodes of Ranvier also result in significant metabolic savings: far less energy must be expended to maintain the ionic gradients that underlie action potential generation and propagation. Myelinating glia actively sculpt the functional organization of axons such that in both the PNS and CNS axons are subdivided into four major domains: nodes of Ranvier, paranodes, juxtaparanodes, and internodes (Fig. 1C). Nodes are characterized by the high density clustering of voltage-gated Na+ channels responsible for regeneration and propagation of the action potential. A complex set of glia-derived extracellular matrix molecules, axonal cell adhesion molecules, and cytoskeletal proteins function as one of two glia-dependent mechanisms that cluster Na+ channels (32.Susuki K. Chang K.J. Zollinger D.R. Liu Y. Ogawa Y. Eshed-Eisenbach Y. Dours-Zimmermann M.T. Oses-Prieto J.A. Burlingame A.L. Seidenbecher C.I. Zimmermann D.R. Oohashi T. Peles E. Rasband M.N. Three mechanisms assemble central nervous system nodes of Ranvier.Neuron. 2013; 78: 469-482Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 33.Feinberg K. Eshed-Eisenbach Y. Frechter S. Amor V. Salomon D. Sabanay H. Dupree J.L. Grumet M. Brophy P.J. Shrager P. Peles E. A glial signal consisting of gliomedin and NrCAM clusters axonal Na+ channels during the formation of nodes of Ranvier.Neuron. 2010; 65: 490-502Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar). Flanking the nodes are paranodal junctions where the myelin sheath attaches to the axon; here, paranodes form the largest known intercellular adhesive junction. Paranodes also have lipid raftlike properties that allow them to be purified and analyzed by mass spectrometry (34.Schafer D.P. Bansal R. Hedstrom K.L. Pfeiffer S.E. Rasband M.N. Does paranode formation and maintenance require partitioning of neurofascin 155 into lipid rafts?.J. Neurosci. 2004; 24: 3176-3185Crossref PubMed Scopus (113) Google Scholar); we used this characteristic of the paranodal junctions to identify proteins enriched in this important domain. We found a specialized paranodal cytoskeleton consisting of spectrins in the axon (35.Ogawa Y. Schafer D.P. Horresh I. Bar V. Hales K. Yang Y. Susuki K. Peles E. Stankewich M.C. Rasband M.N. Spectrins and ankyrinB constitute a specialized paranodal cytoskeleton.J. Neurosci. 2006; 26: 5230-5239Crossref PubMed Scopus (136) Google Scholar) and ankyrins on the glial side of the paranode (36.Chang K.J. Zollinger D.R. Susuki K. Sherman D.L. Makara M.A. Brophy P.J. Cooper E.C. Bennett V. Mohler P.J. Rasband M.N. Glial ankyrins facilitate paranodal axoglial junction assembly.Nat. Neurosci. 2014; 17: 1673-1681Crossref PubMed Scopus (66) Google Scholar). Paranodal junctions and their associated cytoskeleton function both to isolate nodal currents from internodal regions and as the second glia-dependent mechanism for the clustering of axonal ion channels (37.Chang K.J. Rasband M.N. Excitable domains of myelinated nerves: axon initial segments and nodes of Ranvier.Curr. Top. Membr. 2013; 72: 159-192Crossref PubMed Scopus (32) Google Scholar, 38.Zhang C. Susuki K. Zollinger D.R. Dupree J.L. Rasband M.N. Membrane domain organization of myelinated axons requires βII spectrin.J. Cell Biol. 2013; 203: 437-443Crossref PubMed Scopus (57) Google Scholar). Adjacent to the paranodal junctions and beneath the myelin sheath is the juxtaparanode, a region defined by the clustering of Kv1 K+ channels. These K+ channels are also clustered through axon-glia interactions, but their physiological functions remain largely enigmatic (39.Rasband M.N. It's ‘juxta’ potassium channel.J. Neurosci. Res. 2004; 76: 749-757Crossref PubMed Scopus (71) Google Scholar). Finally, the vast majority of the myelinated axon consists of internode with very low densities of ion channels; it is this low density that confers an increase in membrane resistance on axons relative to nodes. Although these axonal domains consist of different sets of cell adhesion molecules, ion channels, and cytoskeletal proteins, all axonal domains are assembled and maintained by myelinating glia. Efforts to define the proteome of each domain have met with varying degrees of success. Because of their detergent insolubility and strong association with the axonal cytoskeleton, nodes and paranodes have proven to be resistant to typical immunoaffinity isolation of protein complexes. In contrast, juxtaparanodal protein complexes are readily solubilized and purified. We previously used immunoprecipitation followed by mass spectrometry to identify new components of juxtaparanodes (40.Ogawa Y. Oses-Prieto J. Kim M.Y. Horresh I. Peles E. Burlingame A.L. Trimmer J.S. Meijer D. Rasband M.N. ADAM22, a Kv1 channel-interacting protein, recruits membrane-associated guanylate kinases to juxtaparanodes of myelinated axons.J. Neurosci. 2010; 30: 1038-1048Crossref PubMed Scopus (94) Google Scholar). Because myelinated axons are completely isolated from the extracellular space except at the nodes of Ranvier, myelinating glia must also provide metabolic support to axons. Current evidence suggests that oligodendrocytes and Schwann cells provide a variety of metabolites including cholesterol, lactate, and glycogen to axons (41.Hirrlinger J. Nave K.A. Adapting brain metabolism to myelination and long-range signal transduction.Glia. 2014; 62: 1749-1761Crossref PubMed Scopus (78) Google Scholar). In support of the idea that myelinating glia provide lactate to axons for an energy source, loss of lactate transporters from oligodendrocytes results in axon damage and degeneration (42.Lee Y. Morrison B.M. Li Y. Lengacher S. Farah M.H. Hoffman P.N. Liu Y. Tsingalia A. Jin L. Zhang P.W. Pellerin L. Magistretti P.J. Rothstein J.D. Oligodendroglia metabolically support axons and contribute to neurodegeneration.Nature. 2012; 487: 443-448Crossref PubMed Scopus (1046) Google Scholar). Recent experiments to determine the response of myelinating glia to activity or learning paradigms revealed that myelination is also plastic and can change in adults, not just during early development. For example, one study showed that development of new myelin sheaths is required for mice to learn how to run on a complex running wheel with irregularly spaced rungs (43.McKenzie I.A. Ohayon D. Li H. de Faria J.P. Emery B. Tohyama K. Richardson W.D. Motor skill learning requires active central myelination.Science. 2014; 346: 318-322Crossref PubMed Scopus (676) Google Scholar). This remarkable result proves that some forms of learning require the development of new myelin segments in the adult brain and that this is an activity-dependent phenomenon. One can speculate that the addition of new myelin segments facilitates conduction velocity in specific circuits or alters the timing of action potential arrival. The signals that promote these plastic changes remain completely unknown. The intimate interactions between myelinating glia and axons are also subject to disruption by disease or injury. De- or dysmyelination can result from genetic (e.g. Charcot-Marie-Tooth peripheral neuropathies or Pelizaeus-Merzbacher CNS hypomyelinating disease), autoimmune (e.g. PNS demyelinating Guillain-Barré syndrome or CNS demyelinating multiple sclerosis), metabolic (diabetic neuropathy), mechanical (spinal cord injury and carpal tunnel syndrome), or hypoxic-ischemic insults (stroke and neonatal hypoxia-ischemia). There are currently no cures for demyelinating diseases or injuries. A major consequence of demyelination is the loss of axonal support, which in turn leads to axon degeneration and permanent loss of function and disability (44.Trapp B.D. Peterson J. Ransohoff R.M. Rudick R. Mörk S. Bö L. Axonal transection in the lesions of multiple sclerosis.N. Engl. J. Med. 1998; 338: 278-285Crossref PubMed Scopus (3471) Google Scholar). Thus, treatments for demyelinating diseases and injuries are an acute need and the subject of much current attention. Proteomic analyses of myelin from different demyelinating disease models may provide insights into pathogenesis and potential treatments for these diseases. Microglia have traditionally been viewed primarily as the brain's resident immune cell, and their functions during disease and injury have been studied extensively (45.Hanisch U.K. Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain.Nat. Neurosci. 2007; 10: 1387-1394Crossref PubMed Scopus (2743) Google Scholar). In their resting state, microglia are highly ramified cells with very elaborate thin processes that extend branches to surveil a defined territory (Fig. 1D). After injury, microglia undergo dramatic changes in shape and protein expression to protect the brain. Furthermore, microglia migrate to sites of injury where they release cytokines and phagocytose debris and dead and dying cells. After injury, microglia can strip dysfunctional synapses. Intriguingly, dysfunction or loss of microglia can also result in behavioral deficits and impaired learning-dependent synaptic plasticity (46.Park" @default.
• W1609916908 created "2016-06-24" @default.
• W1609916908 creator A5083792674 @default.
• W1609916908 date "2016-02-01" @default.
• W1609916908 modified "2023-10-09" @default.
• W1609916908 title "Glial Contributions to Neural Function and Disease" @default.
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