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Morphology of Glial Cells

3.1 Astrocytes

Astrocytes (literally 'star-like cells') are the most numerous and diverse glial cells in the CNS. Some astrocytes indeed have a star-like appearance, with several primary (also called stem) processes originating from the soma, although astrocytes come in many different guises. An archetypal morphological feature of astrocytes is their expression of intermediate filaments, which form the cytoskeleton. The main types of astroglial intermediate filament proteins are Glial Fibrillary Acidic Protein (GFAP) and vimentin; expression of GFAP is commonly used as a specific marker for identification of astrocytes. The normal levels of GFAP expression, however, vary quite considerably: for example, GFAP is expressed by virtually every Bergmann glial cell in the cerebellum, whereas only about 15-20 per cent of astrocytes express GFAP in the cortex and hippocampus of mature animals.

Morphologically, the name astroglial cell is an umbrella term that covers several types of glial cell (Figures 3.1 and 3.2). The largest group are the 'true' astrocytes, which have the classical stellate morphology and comprise protoplasmic astrocytes and fibrous astrocytes of the grey and white matter, respectively. The second big group of astroglial cells are the radial glia, which are bipolar cells with an ovoid cell body and elongated processes. Radial glia usually produce two main processes, one of them forming endfeet on the ventricular wall and the other at the pial surface. Radial glia are a common feature of the developing brain, as they are the first cells to develop from neural progenitors; from very early embryonic stages radial glia also form a scaffold, which assist in neuronal migration. After maturation, radial glia disappear from many brain regions and transform into stellate astrocytes, although radial glia remain in the retina (Müller glia) and cerebellum (Bergmann glia). In addition to the two major groups of astroglial cells, there are smaller populations of specialized astroglia localized to specific regions of the CNS, namely the velate astrocytes of the cerebellum, the interlaminar astrocytes of the primate cortex, tanycytes (found in the periventricular organs, the hypophysis and the raphe part of the spinal cord), pituicytes in the neurohypophysis, and perivascular and marginal astrocytes. Finally, brain astroglia also

Ependymocyte

Figure 3.1 Morphological types of astrocytes; Ia - pial tanycyte; Ib - vascular tanycyte; II - radial astrocyte (Bergmann glial cell); III - marginal astrocyte; IV - protoplasmic astrocyte; V - velate astrocyte; VI - fibrous astrocyte; VII - perivascular astrocyte; VIII - interlaminar astrocyte; IX - immature astrocyte; X - ependymocyte; XI - choroid plexus cell. (From: Rechenbach A, Wolburg H (2005) Astrocytes and ependymal glia, In: Neuroglia, Kettenmann H & Ransom BR, Eds, OUP, p. 20.)

Figure 3.1 Morphological types of astrocytes; Ia - pial tanycyte; Ib - vascular tanycyte; II - radial astrocyte (Bergmann glial cell); III - marginal astrocyte; IV - protoplasmic astrocyte; V - velate astrocyte; VI - fibrous astrocyte; VII - perivascular astrocyte; VIII - interlaminar astrocyte; IX - immature astrocyte; X - ependymocyte; XI - choroid plexus cell. (From: Rechenbach A, Wolburg H (2005) Astrocytes and ependymal glia, In: Neuroglia, Kettenmann H & Ransom BR, Eds, OUP, p. 20.)

Astrocyte Ependymocyte
Figure 3.2 Miiller cells from the retina of different species - Golgi stained cells as drawn by S. Ramon y Cajal

include several types of cells that line the ventricles or the subretinal space, namely ependymocytes, choroid plexus cells and retinal pigment epithelial cells.

1. Protoplasmic astrocytes are present in grey matter. They are endowed with many fine processes (on average ~50 ^m long), which are extremely elaborated and complex. The processes of protoplasmic astrocytes contact blood vessels, forming so called 'perivascular' endfeet, and form multiple contacts with neurones. Some protoplasmic astrocytes also send processes to the pial surface, where they form 'subpial' endfeet. Protoplasmic astrocyte density in the cortex varies between 10000 and 30000 per mm3; the surface area of their processes may reach up to 80000 ^m2, and cover practically all neuronal membranes within their reach.

2. Fibrous astrocytes are present in white matter. Their processes are long (up to 300 ^m), though much less elaborate compared to protoplasmic astroglia. The processes of fibrous astrocytes establish several perivascular or subpial endfeet. Fibrous astrocyte processes also send numerous extensions ('perinodal' processes) that contact axons at nodes of Ranvier, the sites of action potential propagation in myelinated axons. The density of fibrous astrocytes is ~200 000 cell per mm3.

3. The retina contains specialized radial glia called Müller cells, which make extensive contacts with retinal neurones. The majority of Müller glial cells have a characteristic morphology (Figure 3.2), extending longitudinal processes along the line of rods and cones. In certain areas of retina, e.g. near the optic nerve entry site, Müller cells are very similar to protoplasmic astrocytes. In human retina, Müller glial cells occupy up to 20 per cent of the overall volume, and the density of these cells approaches 25 000 per mm2 of retinal surface area. Each Müller cell forms contacts with a clearly defined group of neurones organized in a columnar fashion; a single Müller cell supports ~16 neurones in human retina, and up to 30 in rodents.

4. The cerebellum contains specialized radial glia called Bergmann glia. They have relatively small cell bodies (~15 ^m in diameter) and 3-6 processes that extend from the Purkinje cell layer to the pia. Usually several (~8 in rodents) Bergmann glial cells surround a single Purkinje neurone and their processes form a 'tunnel' around the dendritic arborization of Purkinje neurones. The processes of Bergmann glial cells are extremely elaborated, and they form very close contacts with synapses formed by parallel fibres on Purkinje neurone dendrites; each Bergmann glial cell provides coverage for up to 8000 of such synapses.

5. Velate astrocytes are also found in the cerebellum, where they form a sheath surrounding granule neurones; each velate astrocyte enwraps a single granule neurone. A similar type of astrocyte is also present in the olfactory bulb.

6. Interlaminar astrocytes are specific for the cerebral cortex of higher primates. Their characteristic peculiarity is a very long single process (up to 1 mm) that extends from the soma located within the supragranular layer to cortical layer IV. The specific function of these cells is unknown, although they may be involved in delineating cortical modules spanning across layers.

7. Tanycytes are specialized astrocytes found in the periventricular organs, the hypophysis and the raphe part of the spinal cord. In the periventricular organs, tanycytes form a blood-brain barrier by forming tight junctions with capillaries (the blood-brain barrier is normally formed by tight junctions between the endothelial cells, but those in the periventricular organs are 'leaky', and the tanycytes form a permeability barrier between neural parenchyma and the CSF).

8. Astroglial cells in the neuro-hypophysis are known aspituicytes; the processes of these cells surround neuro-secretory axons and axonal endings under resting conditions, and retreat from neural processes when increased hormone output is required.

9. Perivascular and marginal astrocytes are localized very close to the pia, where they form numerous endfeet with blood vessels; as a rule they do not form contacts with neurones, and their main function is in forming the pial and perivascular glia limitans barrier, which assists in isolating the brain parenchyma from the vascular and subarachnoid compartments.

10. Ependymocytes, choroid plexus cells and retinal pigment epithelial cells line the ventricles or the subretinal space. These are secretory epithelial cells. They have been considered under the umbrella term glia because they are not neurones. The choroid plexus cells produce the CSF which fills the brain ventricles, spinal canal and the subarachnoid space; the ependymocytes and retinal pigment cells are endowed with numerous very small movable processes (microvilli and kinocilia) which by regular beating produce a stream of CSF and vitreous humour, respectively.

3.2 Oligodendrocytes

Oligodendroglia are glial cells with few processes, hence the prefix 'oligo'. The main function of oligodendrocytes (Figure 3.3) is the production of myelin, which insulates axons in the CNS, and assists fast saltatory action potential propagation (the same task is performed by Schwann cells in the PNS).

Oligodendrocytes were initially described by Del Rio Hortega in 1928; he classified these cells into four main phenotypes (I-IV) depending on their morphological appearance, and by the number of their processes and the size of the fibres they contacted. Del Rio Hortega also contemplated the main function of oligo-

Schwann Cells

Figure 3.3 Oligodendrocyte and myelinated axons. Diagrammatic representation of a typical white matter oligodendrocyte based on intracellular dye-filled cells and electron microscopy. Each oligodendrocyte myelinates as many as 30-50 axons within 20-30 |xm of the cell body. Along the axon, consecutive myelin sheaths separate nodes of Ranvier, the sites of action potential propagation. Each myelin sheath is a large sheet of membrane that is wrapped around the axon to form multiple lamellae and is connected to the cell body by fine processes

Figure 3.3 Oligodendrocyte and myelinated axons. Diagrammatic representation of a typical white matter oligodendrocyte based on intracellular dye-filled cells and electron microscopy. Each oligodendrocyte myelinates as many as 30-50 axons within 20-30 |xm of the cell body. Along the axon, consecutive myelin sheaths separate nodes of Ranvier, the sites of action potential propagation. Each myelin sheath is a large sheet of membrane that is wrapped around the axon to form multiple lamellae and is connected to the cell body by fine processes dendrocytes as producers of myelin for axonal insulation (this role was firmly proven only in 1964, after new electron microscopy techniques were introduced into neuro-histology).

Morphologically, type I and II oligodendrocytes are very similar; they have a small rounded cell body and produce four to six primary processes which branch and myelinate 10 to 30 thin (diameter <2 ^m) axons, each secondary process forming a single internodal myelin segment of approximately 100-200 ^m length, termed the internodal length (along axons, myelin sheaths are separated by nodes of Ranvier, which are small areas of unmyelinated axon where action potentials are generated; hence the distance between nodes is the internode and the length of a myelin segment between two nodes is the internodal length). Type I oligo-dendrocytes can be found in the forebrain, cerebellum, and spinal cord, whereas type II oligodendrocytes are observed only in white matter (e.g. corpus callossum, optic nerve, cerebellar white matter, etc.), where they are the primary cell type. Type III oligodendrocytes have a much larger cell body, and several thick primary processes, which myelinate up to five thick axons (4-15 ^m in diameter), and produce myelin sheaths with approximately 200-500 ^m internodal length; type III oligodendrocytes are located in the cerebral and cerebellar peduncles, the medulla oblongata and the spinal cord. Finally, type IV oligodendrocytes do not have processes, and form a single long myelin sheath (as great as 1000 ^m internodal length) on the largest diameter axons; type IV oligodendrocytes are located almost exclusively around the entrances of the nerve roots into the CNS. During development, types I-IV are likely to originate from common oligodendrocyte progenitor cells (OPCs), which are multipolar cells that contact numerous small diameter premyelinated axons. The factors that regulate the fate of OPCs are unknown, but it seems likely that signals from axons of different calibre regulate oligodendrocyte phenotype divergence. This question is of some importance, because the dimensions of the myelin sheath determine the conduction properties of the axons in the unit, whereby axons with long thick myelin sheaths (type III/IV oligodendrocyte-axon units) conduct faster than those with short thin myelin sheaths (type I/II oligodendrocyte-axon units).

Oligodendrocytes also participate in the development of nodes of Ranvier and determine their periodicity (see Chapter 8).

In addition to these classical myelin-forming oligodendrocytes, a small population of nonmyelinating oligodendrocytes known as 'satellite oligodendrocytes' are present in the grey matter, where they are usually applied to neuronal perikaria. The function of these satellite oligodendrocytes is unknown.

3.3 NG2 expressing glia

In the 1980s, William Stallcup and colleagues identified a new population of cells in the adult CNS using antibodies to a novel chondroitin sulphate proteoglycan, NG2 (one of a series of molecules derived from mixed neurone (N) and glial (G) cultures). These NG2 immunopositive cells express many specific markers of oligodendrocyte progenitor cells (OPCs), e.g. platelet-derived growth factor alpha receptors (PDGFaR), and are generally considered to be oligodendroglial lineage cells. NG2 immunopositive cells do not co-express markers for mature oligodendrocytes (e.g. galactocerebroside, myelin-related proteins) or astrocytes (e.g. GFAP, vimentin, S100/8, or glutamine synthetase). During development, NG2 immunopositive OPCs give rise to both myelinating oligodendrocytes and a substantial population (5-10 per cent of all glia) of NG2 positive cells that persist throughout the white and grey matter of the mature CNS. Hence, these cells are often called 'NG2-glia', and are characterized as having small somata and extending numerous thin, radially oriented processes, which branch two or more times close to their source. In the normal adult CNS, the vast majority (>90 per cent) of NG2-glia are not mitotically active, although they may become so in response to various insults. NG2-glia are able to generate oligodendrocytes during developmental remodelling of the CNS and following demyelination. NG2-glia may also generate neurones and astrocytes. Hence, NG2-glia may serve as multipotent adult neural stem cells. Nonetheless, the substantial majority of NG2-glia in the mature CNS appear to be fully differentiated, but like astrocytes (see below), appear to retain the function of stem cells in the brain throughout maturation and adulthood.

In the grey matter, NG2-glia form numerous contacts with surrounding neurones, and even receive neuronal afferents, which form functional synapses (see Chapter 6). In the white matter, NG2-glia are also characterized by complex morphology - they extend processes along myelinated axons, and often establish contacts with nodes of Ranvier, being in this respect similar to fibrous astrocytes. In addition to contacting neurones, NG2-glia form multiple associations with astro-cytes and oligodendrocytes, and their myelin sheaths, as well as the subpial and perivascular glia limitans, but apparently NG2-glia do not form contacts with each other, and each cell has a 'territory' of about 200-300 ^m in diameter. There is a clear morphological difference between NG2-glia in grey and white matter, whereby the former extend processes in all directions to form a symmetrical radial process arborization, whereas white matter NG2-glia have a polarized appearance and preferentially extend processes along axon bundles.

Physiologically, NG2-glia have several distinguishing properties - they express voltage-gated Na+, Ca2+ and K+ channels (yet they are generally unable to generate action potentials), as well as glutamate and GABA receptors, although not apparently glutamate transporters or glutamine synthetase, which distinguishes them from astrocytes. NG2-glia therefore are likely to actively communicate with neurones, with a particular task to monitor and rapidly respond to changes in neuronal activity. These cells were even named as 'synantocytes' (from Greek awavTw synanto, meaning contact) to distinguish them from NG2 positive OPCs that generate oligodendrocytes during development, and to stress their distinct appearance, physiology and involvement in neuronal-glial interactions in the mature CNS. Notably, NG2-glia are highly reactive and rapidly respond to CNS insults by outgrowth and proliferation of processes. Activated NG2-glia participate in glial scar formation together with astrocytes. It has been postulated that a primary function of NG2-glia in the adult CNS may be to respond rapidly to changes in neural integrity, either to form a glial scar, or to generate neurones, astrocytes or oligodendrocytes, depending on the needs and the signals. NG2-glia are highly suited for these tasks via their multiple contacts with neural and glial elements.

3.4 Schwann cells

There are 4 types of Schwann cells in the PNS: myelinating Schwann cells, nonmyelinating Schwann cells, perisynaptic Schwann cells of the neuromuscular junction and terminal Schwann-like cells of the sensory neurites. All four types of Schwann cells originate from the neural crest (see Chapters 4 and 8) and during development they migrate along axons. Continuous contact with axons is particularly important as Schwann cell precursors die whenever such a contact is lost. With further developmental progress, the precursors turn into immature Schwann cells, which can survive without axons. These immature Schwann cells attach themselves to the nearest axons, which they start to ensheath. Schwann cells associated with a large diameter axon (>1^m) begin to produce myelin and form an internodal myelin segment with a 1:1 ratio of Schwann cell:axon. Schwann cells attached to small diameter axons (<1 ^m) do not form myelin, but produce a membrane sheath around a bundle of axons and separate the axons from each other within the nerve. The factors that regulate the fate of Schwann cells remain unknown, but (like oligodendrocytes) it is likely that these factors are produced by axons, and that axons of different calibre may produce distinct signals aimed at Schwann cells.

Myelinating Schwann cells also participate in forming nodes of Ranvier (see Chapter 8), and extend multiple perinodal processes that fill the nodal gap. Perin-odal processes are internally connected through gap junctions formed by connexin 32 (Cx32). Perinodal processes form nodal gap substance and are involved in regulation of the ionic microenvironment around the node and, most likely, Schwann cell-axon interactions are important in Na+ channels clustering at nodes and in stabilizing the structure of the nodal axonal membrane.

3.5 Microglia

Microglial cells are the immunocompetent cells residing in the CNS. In essence, microglia form the brain immune system, which is activated upon various kinds of brain injuries and diseases. Microglial cells represent about 10 per cent of all glial cells in the brain. Microglia are of a myelomonocytic origin, and the microglial precursor cells appear in the brain during early embryonic development. In the mature CNS, microglial cells may appear in three distinct states: the resting microglia, activated microglia and phagocytic microglia (see Chapter 9).

In the normal brain, microglial cells are present in the resting state, which is characterized by a small soma and numerous very thin and highly branched processes (hence these cells are also often called 'ramified'). The microglial cells reside in all parts of the brain, with the highest densities in the hippocampus, olfactory telencephalon, basal ganglia and substantia nigra. Every individual microglial cell is responsible for a clearly defined territory of about 50 000 ^m3 in volume; the processes of resting cells are never in contact with each other. There is a clear morphological difference between microglial cells residing in the grey versus white matter: the former extend processes in all directions, whereas the processes of the latter are usually aligned perpendicularly to the axon bundles.

Microglial cells are equipped with numerous receptors and immune molecule recognition sites, which make them perfect sensors of the status of the CNS tissue; brain injury is immediately sensed, which initiates the process of activation of microglia. This process turns microglia into an activated (or reactive) state; and some of the activated cells proceed further to become phagocytes. Both reactive microglia and phagocytes provide an active brain defence system (see Chapter 9).

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  • martin
    What is secreted by perisynaptic schwann cells?
    4 years ago

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