glia

glia (or glial cells) and neurons (nerve cells) are the two major types of cells in the nervous system. While neurons are excitable — generating electrical impulses that transmit information throughout the central nervous system (CNS) and the peripheral nervous system (PNS) — glia are non-excitable cells that serve a wide range of essential functions in support of neurons.

The term ‘glia’ was coined by Virchow in 1846 and can be translated as ‘glue’ or ‘putty’. The classical view of glia is that they form the packing material within which nerve cells are embedded, similar to the connective tissue of peripheral organs. Indeed, a major function of glia, recognized a century ago by the great Spanish anatomist Ramón y Cajal, is to provide structural and physical support for neurons. However, glial cells account for half the bulk of the CNS and outnumber neurons 10 to 1: a window with 10 parts putty to 1 part glass would not be very enlightening! In fact, glia are dynamic elements of the nervous system, performing a variety of other essential functions. The different types of glial cells can collectively be considered as supporting and protecting neurons in the healthy brain and also defending it in all forms of pathological insult.

The main kinds of glia are Schwann cells in the PNS; astrocytes and oligodendrocytes in the CNS; and ependymal cells, forming the lining of the ventricles of the brain. In common with neurons, all these glia are produced by cell division in the embryonic neuroectoderm (indeed, early in development some of the dividing stem cells produce both neurons and glia among their ‘daughter’ cells). Unlike neurons, glia can undergo cell division in the adult and are capable of self-renewal and regeneration.

Oligodendrocytes and Schwann cells have, as their main role, the production of the fatty myelin sheaths that insulate many of the fibres or axons of nerve cells, throughout the nervous system. Myelination increases substantially the speed of conduction of nerve impulses (action potentials). Destruction of the myelinating glial cells leads to demyelination, which causes slowing and eventual block of impulse conduction and hence loss of function (both sensation and the control of movement). The results can be devastating, as in the human demyelinating diseases Multiple Sclerosis (MS) and infectious polyneuritis, which respectively affect the CNS and the PNS.

There are many Schwann cells in the PNS and oligodendrocytes in the grey matter of the CNS that do not form myelin, and little is known about their function. In the developing PNS, and following injury and degeneration of peripheral nerve fibres, Schwann cells have an important ‘trophic’ role — meaning that they produce substances (called ‘trophins’) that promote regrowth of the axons. Conversely, for reasons that remain somewhat mysterious, damaged axons in the adult CNS do not spontaneously regenerate (at least not over long distances) and this is partly due to the fact that oligodendrocytes actually produce proteins that inhibit axon growth. It is noteworthy that transplantation of Schwann cells from peripheral nerves into the CNS can promote regeneration of damaged CNS axons in animals, and this procedure is being pursued in the hope of developing new treatments for damage to the human spinal cord and brain.

Astrocytes are star-shaped (stellate) cells with long, radiating extensions or processes (rather like the dendrites of neurons). During development, the primitive nervous system first appears as a tube (the neural tube) running along the back of the embryo. The first astrocytes extend their processes to span the walls of this tube (some of these are called ‘radial glia’). The stem cells that give rise to neurons (neuroblasts) attach themselves to these glia, and the immature nerve cells that they produce migrate along the glial processes to take up their final positions (for instance forming the layers of the cerebral cortex at the head end of the neural tube).

Astrocytes in the developing, and in the injured, nervous system release trophins that encourage proliferation and maturation of other glial cells. In the adult CNS, the processes of astrocytes stretch out to wrap around cerebral blood vessels and induce their cells to stick tightly together, thus playing an important role in maintaining the blood–brain barrier. Astrocytes are also the true ‘glue’ of the brain. Their ramifying processes contain fine, strong filaments, giving the brain its physical framework. They also stretch to the boundaries of the CNS, forming a delicate meshwork, the pia mater, which covers the entire surface, helping to maintain the shape of the brain.

Besides providing structural support, the processes of many astrocytes wrap themselves around the dendrites, cell bodies, and axons of neurons and play an essential role in homeostasis or stabilization of the chemical environment around them. They absorb potassium, which is released by active neurons, and which would, if allowed to build up, depolarize neurons, first causing hyperexcitability — a state of affairs akin to epilepsy — and eventually inexcitability. Astrocytes near synapses also mop up the neurotransmitter glutamate, which, in excess, is also highly toxic to nerve cells. The build-up of glutamate that occurs when blood flow to an area of brain is inadequate (ischemia) or is cut off (stroke) can cause widespread death of neurons in surrounding areas of the brain. Astrocytes absorb other neurotransmitters, including the inhibitory transmitter, gamma-aminobutyric acid (GABA). This helps to terminate the action of a neurotransmitter when it has taken effect at the appropriate synapse, and to ensure that it does not spread and act inappropriately on neighbouring synapses. Astrocytes also synthesize and release nitric oxide (NO), which has a variety of actions on blood vessels and on neurons (possibly even involved in the strengthening of synapses that underlies memory).

Astrocytes are involved in brain metabolism, because they are capable of glycogenesis (conversion of glucose into glycogen for storage) in response to various hormones and to potassium and glutamate. They can produce lactate, which neurons can metabolize. Astrocytes are extensively coupled to each other via areas of leaky membrane. These ‘gap junctions’ allow the passage of calcium, from cell to cell, which spreads in waves, over long distances. These calcium waves can be initiated in response to a variety of physiological and pathological stimuli and in turn regulate many functions of astrocytes, including their response to injury.

Ramón y Cajal noted that astrocytes form scar tissue in damaged brains and nowadays we know that this is due to an increase in the production of the protein (GFAP) that makes up their filaments. The glial scar isolates undamaged brain areas from the site of injury and has a protective role, but it is also believed to inhibit regeneration of axons.

Finally, there is a class of small glial cells, called microglia, uniformly distributed throughout the CNS, which are not ‘born’ in the nervous system but are formed by transformation of certain white blood cells called macrophages or their precursors, monocytes. Microglia are now thought to be part of the immune system, defending the brain against infection and injury. Like the macrophages from which they develop, they act as scavenging cells or phagocytes — removing debris in the developing or injured CNS. Again like macrophages, they can ‘digest’ foreign proteins (parts of viruses or bacteria, for example) and display fragments of them on the outer surface of their membranes (called antigen presentation). These antigen fragments then stimulate certain white blood cells to produce antibodies to the foreign protein. Microglia also, on activation, secrete various enzymes and other molecules that can attack foreign material (proteases, cytokines, reactive oxygen species, and nitric oxide) in the brain. The presumed function of this reaction is to protect the CNS from immunological insult, but it can be damaging. It might, for example, be a factor in killing oligodendrocytes, and hence triggering demyelination in Multiple Sclerosis, an autoimmune disorder.

Arthur M. Butt

Bibliography

Ransom, B. R. and and Kettenmann, H. (1995). Neuroglia. Oxford University Press.

See also brain; central nervous system; myelin.