Shapes and Roles of Glial Cells

Astrocyte

The Astrocyte is a large cell with many stellar-like processes (hence the name, after Latin, astrum, for star). Astrocytes provide extensive structural and physiological support of neurons in the central nervous system. The star-like projections of this glial cell form a matrix within which neurons may function. These projections wrap around adjacent capillaries and touch neighboring neurons, acting as a relay for nutrients from the blood stream to the neuron. Recent evidence indicates that the astrocyte absorbs glucose from the blood and converts it into the more easily metabolized lactate molecule. The lactate is then passed along to the mitochondria of a neuron for use in energy production. The astrocyte also has limited capacity to convert glucose to its storage form of glycogen for neuronal use during hypogylcemic conditions (i.e., when blood sugar is low). Astrocytes help to maintain the appropriate ionic composition of extracellular fluid surrounding neurons, by absorbing excess potassium and other larger molecules. As we shall discuss in Tutorials 5 and 6, this is a very important function.

In the aftermath of damage to the central nervous system, for example following stroke, both astrocytes and microglia release chemicals that promote the growth of axons and dendrites of healthy neurons in the damaged area. This mechanism may underlie the recovery of function that does occur following tissue damage. There are, however, several factors working against this restorative effect. For example, astrocytes form scar tissue in the aftermath of tissue damage. This tissue fills-in the space previously occupied by the dead neurons. A regenerating axon is unable to pierce this dense tissue, thus limiting the ability of neurons to regenerate in the central nervous system. In addition, astrocytes release a chemical that encourages an axon to sprout terminal endings rather than to grow in length. This also impedes the central nervous system's ability to recover function following damage.

In the 1-3 days following damage to CNS tissue, nitric oxide is released. This nitric acid kills the neurons that are weakened but not yet dead. Knowledge of this mechanism has led to new medical interventions that help to reduce the amount of neuronal damage following cerebral strokes.

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Astrocytes, it turns out, are highly communicative (Parent, 1996; Vesce, Bezzi & Volterra, 1999). Recent evidence indicates reciprocal communication between separate astrocytes and between astrocytes and neurons. The classic view of astrocytes as somewhat passive supporters of neuronal activity is changing, with the possibility that these populous cells of the nervous system play a much more active role in central nervous system function. A large number of signal proteins have been identified in the membranes of astrocytes. These proteins act as channels for the movement of ions and as receptors for neurotransmitters, as is the case for neurons. The functional significance of these channels and receptors is unclear at this time.

Some channels in the astrocyte membrane are specialized to absorb potassium ions (Verkhratsky & Steinhauser, 2000). As described in Tutorials 5 and 6, neurons pump out potassium ions when they discharge. A delicate balance of these ions inside and outside the neuron is essential to neuronal function. Glial cell absorption of these ions prevents the dangerous build-up of high levels of potassium outside the neurons (Walz, 2000). This glial cell control of potassium levels surrounding neurons serves to modulate the responsiveness of those neurons. This slow modulation of the responsiveness of neurons by glial cells has been associated experimentally with several behavioral effects, including learning and response habituation. (Laming, 2000).

Another class of membrane channels has been identified in glial membrane. These are specialized to absorb neurotransmitters from the synaptic junction between two neurons. As described in Tutorial 11, a synapse is the point of communication between neurons. Molecules called neurotransmitters are essential to this communication process. A glial membrane protein called the glutamate uptake carrier absorbs the neurotransmitter, glutamate, after it has successfully conveyed an electrical signal. This particular carrier protein absorbs both glutamate and sodium ions, while at the same time pumping potassium and hydroxyl ions out of the glial cell. Since high levels of glutamate are toxic to neurons, the glutamate uptake carrier performs a very important function.

A second type of glial channel responds to changes across the cell membrane by opening to allow the passage of sodium ions (Sontheimer, 1994). This same mechanism is essential to the neuron's ability to conduct electrical signals (see Tutorial 7), but its role in glial function is still controversial since it is most widely held that glia cells are not capable of conducting electrical impulses. Some researchers have speculated that protein channels exist in glial membrane simply because they are produced by the glial cell to be exported to surrounding neurons.

A third type of protein channel found in glial membrane responds to the presence of specific molecules; these are called ligand-gated ion channels. This type of protein channel is called a receptor and the ligand or stimulating molecule is called a neurotransmitter. Ligand-gated ion channels identified in glial membrane so far include those responsive to glutamate, gammaaminobutyric acid, and norepinephrine, three neurotransmitters that are very important to neuronal function (Gallo & Russell, 1995). Although we have long known of this type of channel in neuronal membrane, their discovery in glial membrane was surprising to many who have assumed a greater distinction in function for these cell types.

Some very recent evidence, however, from the recordings of electrical activity of single glial cells and neurons in the leech suggest that neuronal activity is more intricately linked with that of glial cells than previously thought (Deitmer et al., 1999; Gunzel & Schlue, 2000). For example, depolarization and hyperpolarization of glial membrane has been measured in response to similar activity in adjacent neurons. These glial membrane responses may be accompanied by changes in the concentration of ions within the glial cells. Amazingly, this interaction between neuronal and glial electrical changes has been measured in association with behavior. Some glial cells respond to the presence of glutamate or electrical stimulation with slow and alternating flows of calcium ions into and then out of the cells. These so-called calcium waves are passed to adjacent glial cells where they make contact. This phenomenon appears to be yet another method whereby glial cells communicate with surrounding neurons.

Glial cells play an active role during development of the brain (Bentivoglio & Mazzarello, 1999). Glial cells from "strands" that physically define the appropriate route for the developing neurons. Maturing neurons literally hug these glial strands as they migrate along to their destination. Glial cells also supply neurotrophic factors. One in particular, called nerve growth factor stimulates the new growth of neurons and otherwise maintains conditions necessary to their survival during development.

New neurotropic factors are discovered on an ongoing basis. Two recently discovered candidates provide hope for clinical application. One of these is specialized to support the growth of dopamine neurons (Collier & Martin, 1993; Lapchak, 1998) Some dopamine neurons are defective in Parkinson's Disease, a neurological disease affecting motor function. Platelet-derived growth factor signals the precursor cells of oligodendrocytes to divide and mature with the development of new axons (Dubois-Dalcq & Murray, 2000; Webster, 1997). This growth factor may eventually prove useful in the treatment of multiple sclerosis, a demyelinating disease of fatal consequence.

References

Bentivoglio, M. & Mazzarello, P. (1999). The history of radial glia. Brain Research Bulletin, 49(5), 305-315.

Collier, T.J. & Martin, P.N. (1993). Schwann cells as a source of neurotrophic activity for dopamine neurons. Experimental Neurology, 124(1), 129-133.

Dubois-Dalcq, M. & Murray, K. (2000). Why are growth factors important in oligodendrocyte physiology? Pathological Biology (Paris), 48(1), 80-86.

Dunzel, D. & Schlue, W.R. (2000). Mechanisms of Mg2+ influx, efflux and intracellular muffling in leech neurones and glial cells. Magnesium Research, 13(2), 123-138.

Deitmer, J.W., Rose, C.R., Munsch, T., Schmidt, J., Nett, W., Schneider, H.P. & Lohr, C. (1999). Leech giant glial cell: functional role in a simple nervous system. Glia, 28(3), 175-182.

Gallo, V. & Russell, J.T. (1995). Excitatory amino acid receptors in glia: different subtypes for distinct functions? Journal of Neuroscience Research, 42(1), 1-8.

Laming, P.R. (2000). Potassium signalling in the brain: its role in behaviour. Neurochemistry International, 36(4-5), 271-290.

Lapchak, P.A. (1998). A preclinical development strategy designed to optimize the use of glial cell line-derived neurotrophic factor in the treatment of Parkinson's disease. Movement Disorders, 13(Suppl. 1), 49-54.

Parent, A. (1996). Carpenter's human neuroanatomy (9th ed.). London: Williams & Wilkins.

Sontheimer, H. (1994). Voltage-dependent ion channels in glial cells. Glia, 11(2), 156-172.

Verkhratsky, A. & Steinhauser, C. (2000). Ion channels in glial cells. Brain Research Reviews, 32(2-3), 380-412.

Vesce, S., Bezzi, P. & Volterra, A. (1999). The highly integrated dialogue between neurons and astrocytes in brain function. Science Progress, 82(Pt.3), 251-270.

Walz, W. (2000). Role of astrocytes in the clearance of excess extracellular potassium. Neurochemistry International, 36(4-5), 291-300.

Webster, H.D. (1997). Growth factors and myelin regeneration in multiple sclerosis. Multiple Sclerosis, 3(2), 113-120.