Astrocytes are one of several types of neuroglial cell, the others being oligodendrocytes, Schwann cells, radial glia, satellite cells and ependymal cells. Glial cells have long been known to perform specialized functions in the nervous system. Oligodendrocytes form the myelin sheath which insulates nerve fibres in the central nervous system; Schwann cells form myelin sheaths around peripheral nerve fibres; radial glia guide the migration of neurons during corticogenesis; satellite cells control the chemical environment surrounding peripheral neurons; and ependymal cells form the lining of the cerebral ventricles and produce and secrete cerebrospinal fluid.
The function of astrocytes, however, remained a mystery for a long time. It has always been thought that they form an inert scaffold which supported neurons. This is largely due to Rudolph Virchow, who regarded glial cells as part of a non-cellular connective tissue. Virchow introduced the term “neuroglia” in a paper published in a German medical journal in 1856:
…According to my investigations, the ependyma [of the cerebral ventricles] consists not only of an epithelium, but essentially a layer of connective tissue covered with epithelium. Although it can be separated without difficulty from the surface, yet it does not constitute an isolated membrane…but only a layer of interstitial connective tissue of the brain substance which is prominent on the surface. This connective substance, which is in the brain, the spinal cord, and the special sense nerves, is a kind of glue (neuroglia) in which the nervous elements are planted…in the fresh state, a fine-grained very plentiful substance with longish, oval and fairly large nuclei can be found, which was earlier mistaken for a special kind of nerve substance. The nuclei are, however, contained in very soft and fragile cells, as can be seen at times in fresh material and even more clearly in that which has been artificially hardened.
Virchow’s description of glial cells as “nerve glue” was very influential – it stuck for over 100 years, and the idea that astrocytes provide support for neurons in various ways became entrenched. It is true that astrocytes synthesize growth factors that are vital for regulating the structure, proliferation, differentiation and survival of neuronal populations. But in recent years it has become apparent that astrocytes play other roles, and the view of astrocytes as inert elements has changed. It is now known that astrocytes play diverse and crucial functions in the brain, including the control of synapse formation, modulation of synaptic transmission, and the regulation of adult neurogenesis. Abnormally functioning astrocytes have also been implicated in a large number of pathological conditions. Below I will focus on the role of astrocytes in intercellular communication.
Astrocytes are broadly divided into two types. Protoplasmic astrocytes are found in the grey matter and have numerous branched processes; it is these astrocytes which possess endfeet that envelop synapses (as mentioned in more detail below). The white matter contains fibrous astrocytes which have long thin and unbranched processes which wrap themselves around Nodes of Ranvier. However, this dichotomy is a gross oversimplification – there are many different types of astrocytes.
It was previously thought that astrocytes are organized somewhat haphazardly, with their processes interdigitating. But several recent studies, in which adjacent hippocampal astrocytes were microinjected with fluorescent dyes of different colours, show that their arrangement is highly organized, with each astrocyte occupying a discrete anatomical domain (left). The domain of each astrocyte encompasses a region of microvasculature, as well as hundreds or thousands of synapses. And, apart from the interaction of processes from adjacent astrocytes, there is very little overlap between the cells. Each domain contains autonom- ously controlled microdomains, within which astrocytic lamellipodia, filopodia, and endfeet can be found.
Astrocytes regulate synaptic transmission in a number of ways, and their ability to do so is partly due to this highly ordered arrangement. For example, in the rodent barrel cortex, a part of the somatosensory cortex which receives sensory inputs from the whiskers, sensory stimulation, or lack of it, can strengthen or weaken synaptic connections, respectively. This activity-dependent plasticity is now known to be regulated by astrocytes. Last year, Genoud, et al showed that astrocytic endfeet are closely apposed to the dendritic spines of cortical cells, and that the endfeet envelop the spines more tightly in response to hyperstimulation of the whiskers. These morphological change were highly dynamic, occurring within minutes of stimulation. Astrocytes are known to express transporters for glutamate and other neurotransmitters; the encircling of dendritic spines observed may increase the rate at which glutamate released from the whisker barrel neurons is taken up by the astrocytes. (Impaired glutamate re-uptake by astrocytes has also been implicated in the excitotoxicity associated with various neurodegenerative disorders.)
As well as expressing neurotransmitter transporters, astrocytes also express neurotransmitter receptors and voltage-gated sodium and potassium channels. But, because they do not generate action potentials, astrocytes were thought to be incapable of intercellular communication. This is now known not to be the case. Astrocytes in a given area of the brain form a syncytium in which their electrical activity is coupled via gap junctions (electrical synapses). They are now known to listen in on inter-neuronal communic- ation at synapses, and it is now clear that they also make their own contributions to the conversation. They also communicate with each other, with other types of glial cells, and with blood vessels in the brain. Although incapable of generating action potentials, astrocytes are excitable, and, like neurons, they respond to excitation with increases in intracellular calcium ion concentration.
In 1994, it was discovered that astrocytes synthesize what have been termed ‘gliotransmitters’. These include glutamate, ATP and various cytokines and neuropeptides; by releasing these chemicals, astrocytes modulate both excitatory and inhibitory synaptic transmission. Gliotransmitters are contained within structures called synaptic-like microvesicles (SLMVs). These are similar to the synaptic vesicles found in glutamatergic neurons. In astrocytic processes that straddle synapses, loosely arranged groups of SLMVs are located just beneath the cell membrane. Gliotransmitters can be released in the same way as neurotransmitters are released by nerve cells – by exocytosis. Astrocytic exocytosis is dependent on calcium and is mediated by the SNAP and SNARE proteins, as is the case in neurons. It appears that astrocytes are also able to release their transmitters by active molecular transport.
Earlier this month, in the Proceedings of the National Academy of Sciences, Bowser et al reported that the release of transmitters from astroctyes can occur by both full and partial – or “kiss-and-run” – exocytosis. And, in this month’s edition of Nature Neuroscience, a paper provides evidence that astrocytic exocytosis is involved in modulating the strength of synapses formed by neurons. Jourdain et al used the patch-clamp technique to record the electrical activity of astrocyte-granule cell pairs in the dentate gyrus of the rat hippocampus. Electrical stimulation of the astrocytes triggered an increase in the electrical activity of the granule cells paired with them. This increases the probability that the granule cells will release their neurotransmitters, and therefore potentiates synaptic transmission in the hippocampus by strengthening the synapses. Ultrastructural analysis revealed a correlation between the distribution of SLMVs containing glutamate in astrocytic processes and the arrangement of NMDA receptors in the associated nerve terminals.
Research into the functions of astrocytes is ongoing, and it seems that the recent discoveries are just the tip of the iceberg. There is little doubt that other surprising functions of astrocytes remain to be discovered, and that these cells are the real stars of brain function.
Bowser, D. N. & Khakh, B. S. (2007). Two forms of single-vesicle astrocyte exocytosis imaged with internal reflection fluorescence microscopy. Proc. Nat. Acad. Sci. DOI: 10.1073/pnas.0607625104 [Abstract]
Jourdain, P. et al. (2007). Glutamate exocytosis from astrocytes controls synaptic strength. Nat. Neurosci. DOI: doi:10.1038/nn1849. [Abstract]
Volterra, A. & Meldolesi, J. (2005). Astrocytes, from brain glue to communicating elements: The revolution continues. Nat. Rev. Neurosci. DOI: 10.1038/nrn1722. [Full text]