The scoop on the fly brain: glial engulfment functions in Drosophila

Glial cells provide support and protection for neurons in the embryonic and adult brain, mediated in part through the phagocytic activity of glia. Glial cells engulf apoptotic cells and pruned neurites from the developing nervous system, and also clear degenerating neuronal debris from the adult brain after neural trauma. Studies indicate that Drosophila melanogaster is an ideal model system to elucidate the mechanisms of engulfment by glia. The recent studies reviewed here show that many features of glial engulfment are conserved across species and argue that work in Drosophila will provide valuable cellular and molecular insight into glial engulfment activity in mammals.     

Glial cells in the central nervous system of earthworm, Eisenia fetida

Glial elements in the central nervous system of Eisenia fetida were studied at light- and electron microscopic level. Cells were characterized with the aid of toluidine blue, Glial Fibrillary Acidic Protein (GFAP), S100 staining. We identified neurilemmal-, subneurilemmal-, supporting-nutrifying- and myelinsheath forming glial cells. Both neuronal and non-neuronal elements are S100-immunoreactive in the CNS. Among glial cells neurilemmal and subneurilemmal cells are S100-immunopositive. With the antibody against the S100 protein one band is visible at 15 kDa. GFA P-immunopositive supporting-nutrifying glial cells are localized around neurons and they often appear as cells with many vacuoles. GFA P-positive cell bodies of elongated neurilemmal glial cells are also visible. Western blot analysis shows a single 57 kDa GFA P immunoreactive band in the Eisenia sample. At ultrastructural level contacts between neuronal and glial cells are recognizable. Glial cell bodies and their filopodia contain a granular and vesicular system. Close contacts between neuronal cell membranes and glial filopodia create a special environment for material transport. Vesicles budding off glial cell granules move towards the cell membranes, probably emptying their content with kiss and run exocytosis. The secreted compounds in return may help neuronal survival, provide nutrition, and filopodia may also support neuronal terminals.     

GLIA: listening and talking to the synapse

Glial cells are emerging from the background to become more prominent in our thinking about integration in the nervous system. Given that glial cells associated with synapses integrate neuronal inputs and can release transmitters that modulate synaptic activity, it is time to rethink our understanding of the wiring diagram of the nervous system. It is no longer appropriate to consider solely neuron-neuron connections; we also need to develop a view of the intricate web of active connections among glial cells, and between glia and neurons. Without such a view, it might be impossible to decode the language of the brain.     

Glial cells more than support cells?

Glial cells are the most abundant cells in the human brain and have long been considered as passive supporting cells for neurons. In contrast to the extensive studies on various neuronal functions in the nervous system, we still have limited knowledge about glial cells. Recently a number of pioneering studies have provided convincing evidence that glia play active roles in development and function of the central nervous system. This review discusses recent advances in our understanding of the molecular mechanisms underlying glial cell differentiation. We then highlight some of the novel findings about glial function, i.e. the role of glia in synaptogenesis and the intricate relationship between astrocytes and adult neural stem cells. Finally, we summarize the emerging studies that implicate abnormalities in the formation or maintenance of glia leading to severe brain diseases, such as Alexander disease, glioblastoma and multiple sclerosis, and potential therapeutic strategies to tackle these diseases.     

Combined immunostaining of neurofilaments, neuron specific enolase, GFAP and S-100. A possible means for assessing the morphological and functional status of the enteric nervous system

Neurofilaments, part of the cytoskeletal network, and neuron specific enolase, a major enzyme in glycolysis, are both present in central and peripheral neurons. Glial fibrillary acidic protein and S-100, on the other hand, are soluble proteins which are found exclusively in the supportive cells of the nervous system, i.e. the glial cells. Examination was made, using immunocytochemistry, of all main areas of the gastrointestinal tract of three mammalian species, rat, pig and man. By applying serial tissue sectioning, it was possible to study the relative occurrences of the two neuronal markers in the same cell bodies and to examine the relationships of the neurons with the glial cells as revealed by the antibodies to glial fibrillary acidic protein and S-100. Both neurofilaments and neuron specific enolase were localised to an extensive system of enteric nerves, with the level of neuron specific enolase-immunoreactivity showing greater variability than that observed using antibodies to neurofilaments. Comparison of the occurrence of neuron specific enolase and neurofilament immunoreactivity in serially sectioned neuronal cell bodies revealed that a minor population stained only with antibodies to neurofilaments. The equivocal or absent neuron specific enolase-immunoreactivity in some perikarya may reflect variations in functional status within the nervous system. Glial fibrillary acidic protein- and S-100-immunoreactivities were confined to glial cells which, in this normal tissue, were always in close association with the neurons.(ABSTRACT TRUNCATED AT 250 WORDS)     

Signaling in glial development: differentiation migration and axon guidance.

Glial cells have diverse functions that are necessary for the proper development and function of complex nervous systems. During development, a variety of reciprocal signaling interactions between glia and neurons dictate all parts of nervous system development. Glia may provide attractive, repulsive, or contact-mediated cues to steer neuronal growth cones and ensure that neurons find their appropriate synaptic targets. In fact, both neurons and glia may act as migrational substrates for one another at different times during development. Also, the exchange of trophic signals between glia and neurons is essential for the proper bundling, fasciculation, and ensheathement of axons as well as the differentiation and survival of both cell types. The growing number of links between glial malfunction and human disease has generated great interest in glial biology. Because of its relative simplicity and the many molecular genetic tools available, Drosophila is an excellent model organism for studying glial development. This review will outline the roles of glia and their interactions with neurons in the embryonic nervous system of the fly.     

编者按: 神奇的“胶水”细胞

胶质细胞是一类神经系统中区别于神经元的一大类细胞，其数量是神经元的10~50倍。而且在相当长的一段时间胶质细胞也被认为是神经系统中的一种“胶水”，仅起到黏结神经元和填充神经系统的作用。随着近几十年神经科学的发展，神经生物学家们发现，胶质细胞的功能多种多样，并参与记忆、认知、神经发育性和退行性疾病，甚至衰老等高级功能。通过PubMed查询，中国胶质细胞相关论文的十年增长率为270%，远远高于全球平均增长率140%，说明中国在胶质细胞方面的研究势头非常强劲。本期《生物化学与生物物理进展》刊出了围绕胶质细胞的20余篇论文。涵盖胶质细胞的生理功能和病理功能的各个方面。本期的刊行将有利于推动国内胶质细胞科学研究，并为中国脑计划提供参考。     

The role of glial cells in synaptic function

Glial cells represent the most abundant cell population in the central nervous system and for years they have been thought to provide just structural and trophic support to neurons. Recently, several studies were performed, leading to the identification of an active interaction between glia and neurons. This paper focuses on the role played by glial cells at the level of the synapse, reviewing recent data defining how glia is determinant in synaptogenesis, in the modulation of fully working synaptic contacts and in synaptic plasticity.     

Glia development in the embryonic CNS of Drosophila.

Glial cells are pivotal players during the development and function of complex nervous systems. In Drosophila, recent genetic analyses have revealed several genes that control differentiation and function of CNS glial cells and their interactions with neurons can be studied in detail at the CNS midline, where it is essential for the correct establishment of the commissural axon pattern.     

Adult insect glial culture: Activation, substrate effects and proliferation

Glial cells from an adult insect, Periplaneta americana, have been grown in neurone-free cultures. No growth occurred from freshly-excised fragments of abdominal nervous connectives. Vigorous growth was obtained, however, from explants of connectives induced to proliferate by prior exposure to a toxin, ethidium bromide, applied selectively to glial cells in vivo. Glial growth in vitro is dependent upon the initiation of early stages of repair in vivo: this supports the idea that haemocytes which invade the lesion zone immediately after damage are involved in directing proliferation of perineurial and sub-perineurial glia. In contrast, both glial and neuronal cells grew in vitro from explanted abdominal ganglia without prior glial lesioning, indicating that different factors may determine cellular regeneration in this domain. The morphology of the proliferating cells was influenced by the substrate; extensive glial migration was restricted to areas of close contact between cell and substrate surface.     

Initial appearance and regional distribution of the neuron-glia cell adhesion molecule in the chick embryo

This study represents a global survey of the times of the first appearance of the neuron-glia cell adhesion molecule (Ng-CAM) in various regions and on particular cells of the chick embryonic nervous system. Ng-CAM, originally characterized by means of an in vitro binding assay between glial cells and brain membrane vesicles, first appears in development at the surface of early postmitotic neurons. By 3 d in the chick embryo, the first neurons detected by antibodies to Ng-CAM are located in the ventral neural tube; these precursors of motor neurons emit well-stained fibers to the periphery. To identify locations of appearance of Ng-CAM in the peripheral nervous system (PNS), we used a monoclonal antibody called NC-1 that is specific for neural crest cells in early embryos to show the presence of numerous crest cells in the neuritic outgrowth from the neural tube; neither these crest cells nor those in ganglion rudiments bound anti-Ng-CAM antibodies. The earliest neurons in the PNS stained by anti-Ng-CAM appeared by 4 d of development in the cranial ganglia. At later stages and progressively, all the neurons and neurities of the PNS were found to contain Ng-CAM both in vitro and in vivo. Many central nervous system (CNS) neurons also showed Ng-CAM at these later stages, but in the CNS, the molecule was mostly associated with neuronal processes (mainly axons) rather than with cell bodies; this regional distribution at the neuronal cell surface is an example of polarity modulation. In contrast to the neural cell adhesion molecule and the liver cell adhesion molecule, both of which are found very early in derivatives of more than one germ layer, Ng-CAM is expressed only on neurons of the CNS and the PNS during the later epoch of development concerned with neural histogenesis. Ng-CAM is thus a specific differentiation product of neuroectoderm. Ng-CAM was found on developing neurons at approximately the same time that neurofilaments first appear, times at which glial cells are still undergoing differentiation from neuroepithelial precursors. The present findings and those of previous studies suggest that together the neural cell adhesion molecule and Ng-CAM mediate specific cellular interactions during the formation of neuronal networks by means of modulation events that govern their prevalence and polarity on neuronal cell surfaces.     

Glial cells and volume transmission in the CNS

Although synaptic transmission is an important means of communication between neurons, neurons themselves and neurons and glia also communicate by extrasynaptic "volume" transmission, which is mediated by diffusion in the extracellular space (ECS). The ECS of the central nervous system (CNS) is the microenvironment of neurons and glial cells. The composition and size of ECS change dynamically during neuronal activity as well as during pathological states. Following their release, a number of neuroactive substances, including ions, mediators, metabolites and neurotransmitters, diffuse via the ECS to targets distant from their release sites. Glial cells affect the composition and volume of the ECS and therefore also extracellular diffusion, particularly during development, aging and pathological states such as ischemia, injury, X-irradiation, gliosis, demyelination and often in grafted tissue. Recent studies also indicate that diffusion in the ECS is affected by ECS volume inhomogeneities, which are the result of a more compacted space in certain regions, e.g. in the vicinity of oligodendrocytes. Besides glial cells, the extracellular matrix also changes ECS geometry and forms diffusion barriers, which may also result in diffusion anisotropy. Glial cells therefore play an important role in extrasynaptic transmission, for example in functions such as vigilance, sleep, depression, chronic pain, LTP, LTD, memory formation and other plastic changes in the CNS. In turn, ECS diffusion parameters affect neuron-glia communication, ionic homeostasis and movement and/or accumulation of neuroactive substances in the brain.     

Role of Astrocytes in Pain

Over the last decade, a series of studies has demonstrated that glia in the central nervous system play roles in many aspects of neuronal functioning including pain processing. Peripheral tissue damage or inflammation initiates signals that alter the function of the glial cells (microglia and astrocytes in particular), which in turn release factors that regulate nociceptive neuronal excitability. Like immune cells, these glial cells not only react at sites of central and/or peripheral nervous system damage but also exert their action at remote sites from the focus of injury or disease. As well as extensive evidence of microglial involvement in various pain states, there is also documentation that astrocytes are involved, sometimes seemingly playing a more dominant role than microglia. The interactions between astrocytes, microglia and neurons are now recognized as fundamental mechanisms underlying acute and chronic pain states. This review focuses on recent advances in understanding of the role of astrocytes in pain states.     

Glutamate and GABA receptors in vertebrate glial cells

Glial cells of the central nervous system express receptors for the main inhibitory and excitatory neurotransmitters, GABA and glutamate. The glial GABA and glutamate receptors share many properties with the neuronal GABAA and kainate/quisqualate receptors, but are molecularly and, in some aspects, pharmacologically distinct from their neuronal counterparts. The functional role of these receptors is as yet speculative: They have been proposed to control proliferation of astrocytes, serve to balance ion changes at GABAergic synapses, or they could enable the glial cell to detect neuronal synaptic activity.     

Schwann Cell Exosomes Mediate Neuron–Glia Communication and Enhance Axonal Regeneration

The functional and structural integrity of the nervous system depends on the coordinated action of neurons and glial cells. Phenomena like synaptic activity, conduction of action potentials, and neuronal growth and regeneration, to name a few, are fine tuned by glial cells. Furthermore, the active role of glial cells in the regulation of neuronal functions is underscored by several conditions in which specific mutation affecting the glia results in axonal dysfunction. We have shown that Schwann cells (SCs), the peripheral nervous system glia, supply axons with ribosomes, and since proteins underlie cellular programs or functions, this dependence of axons from glial cells provides a new and unexplored dimension to our understanding of the nervous system. Recent evidence has now established a new modality of intercellular communication through extracellular vesicles. We have already shown that SC-derived extracellular vesicles known as exosomes enhance axonal regeneration, and increase neuronal survival after pro-degenerative stimuli. Therefore, the biology nervous system will have to be reformulated to include that the phenotype of a nerve cell results from the contribution of two nuclei, with enormous significance for the understanding of the nervous system in health and disease.     

Glial cells and neurotransmission: an inclusive view of synaptic function

Glial cells throughout the nervous system are closely associated with synapses. Accompanying these anatomical couplings are intriguing functional interactions, including the capacity of certain glial cells to respond to and modulate neurotransmission. Glial cells can also help establish, maintain, and reconstitute synapses. In this review, we discuss evidence indicating that glial cells make important contributions to synaptic function.