- Neuronal activity
- Glia limintans
- Blood–brain barrier
Astrocytes are cells found in the central nervous system: encephalon and spinal cord. Together with oligodendrocytes, microglia, and Schwann cells form the glial cells. For a very long time, astrocytes have been regarded as minor cells in the nervous system when compared with neurons. Astrocyte function appeared to be as housekeepers of neurons and to form barriers in the borders of the central nervous system. However, many and varied functions are ascribed to astrocytes nowadays in normal nervous system, in pathology processes and during development. They are even involved in modulating the information precessed by neurons. It is interesting that during the primate evolution, the ratio of astrocytes/neurons has thought to be increased in the encephalon.
Glial fibrillary acidic protein (GFAP) is a protein specifically found as part of the cytoskeleton of astrocytes. The name astrocyte is because of the star-like morphology of the cytoskeletal intermediate filaments. However, the cell morphology may be variable. For example, those locate in the gray matter are known as protoplasmic astrocytes and those of the white matter are known as fibrous astrocytes. There are also highly specialized astrocytes as Bergmann glia in the cerebellum and Müller glia in the retina (Figure 1).
Protoplasmic astrocytes have cell expansions that can branch several times. The terminal ends of these protrusions are called end-feet, which cover blood vessels, pial surfaces and synapses (one astrocyte may wrap thousands of synapses). Fibrous astrocytes are found in the white matter and have thinner cell expansions with few branches. End-feet of fibrous astrocytes wrap Ranvier nodes and blood vessels of axonal tracts.
Astrocytes are the most abundant glial type in the brain (Figure 2). The number of astrocytes is variable depending on the brain area, but they are about 20 to 25 % of the volume in many brain areas. In cat and rat brains, astrocytes are as numerous as neurons.
Astrocytes are mostly generated during the perinatal period, once the massive production of neurons is over. This behavior has been found in humans and cats. During this period, astrocytes may be differentiated from several sources. For example, in the cerebral cortex, astrocytes can derived from radial glia, ventricle walls, and from NG2 undifferentiated glia. Initially, all these cells become progenitor astrocytes, which differentiate directly into astrocytes or go first through a number of divisions to increase the future local population of mature astrocytes. Astrocytes may also proliferate in adult tissues. Local production of new mature astrocytes in adult periods may come from the mitotic activity of some progenitors that remain inactive and undifferentiated for a long time. During the perinatal period of cats, the ratio glia/neuron is 0.86, whereas in adults is 1.4. It means that the number of astrocytes increases in a way that outnumber neurons.
Compared to neurons, a rather passive function has usually been assigned to astrocytes. They were thought to be involved in neuron homeostasis, mechanical support and contribute to a normal function nervous tissue by isolating synapses (preventing interference between close synapses). Astrocyte cell expansions are around neurons, synapses, and Ranvier nodules. It was found that astrocyte also clear or inactivate extracellular neurotransmitters like glutamate and remove and redistribute extracellular ions such as potassium. All of these contributing to a proper function of synapes. However, it is currently known that astrocytes perform a much more active role in neural transmission.
Astrocytes respond to a number of neurotransmitters, such as monoamines, neuropeptides, GABA, Acetylcholine, nitric oxide and endocannabinoids. There are receptors in the astrocyte plasma membrane for these neurotransmitters.They are no activated synaptically, but in a way called volume transmission. Neurotransmitters released by neurons at the synaptic sites can diffuse from the synaptic cleft, and reach the astrocytes membranes. Astrocytes around and active synapses are able to respond to neuronal activity by rising the inner calcium concentration. Once activated, astrocytes can release molecules known as gliotransmitters, such as glutamate, ATP and adenosine. Receptors for gliotransmitters can be found in neurons and therefore their activity can be modulated. Currently, the model of synapse is the tripartite synapse (Figure 3), which includes presynaptic neuron, postsinaptic neuron and glia that wraps the two of them.
There are other active actions of astrocytes on neurons. They are involved in the differentiation of synapses, and may remove synapses by fagocytosis. During development, astrocytes help establishing neuronal connections and facilitating the axonal migration.
The increase of inner calcium concentration is interesting because astrocytes are connected between each other by gap junctions. Thus, they form a network of connected cytoplasms, as a syncitium, that can synchronize the activity of large populations of astrocytes. The activation of an astrocyte may activate many connected astrocytes. Although the synchronization of astrocytes populations may be interesting for blood flux control in some brain areas, it is not clear yet that this is their real function.
Astrocytes coat the outer surface of the brain and spinal cord (Figure 4). Astrocyte endfeet (monkeys) or whole astrocytes (mice) form a sheet that isolate neurons from meningeal membranes and cover the central nervous system. This outer sheet made by astrocytes is called glia limitans. Astrocytes of glia limitans are anchored to a basal lamina, and the basal lamina to the inner pial membrane. The function of glia limitans is unknown, besides being a physical layer that keeps neurons apart from other non nervous elements. In mice, the glia limitans is made up astrocytes bodies that cover the central nervous system surface, except olfactory bulb and cerebellum. Some authors suggest that astrocytes involved in forming glia limitans are different from protoplasmic and fibrous astrocytes.
P. Hehrlich noticed that the encephalon and spinal cord were special structures because when he injected ink in the blood system all organs got stained, but the central nervous system. There was something that prevent ink to get out of blood vessels in these nervous structures. This is because of the so-called blood-brain barrier, which made up of endothelium, pericytes, basal lamina and endfeet of astrocytes (Figures 5 and 6). In the central nervous system, endothelial cells are very close to each other, more than in any other organ, because they have many cell junctions: tight junctions and gap junctions that seal the intercelullular space. Thus, molecules that want to cross the endothelium need to do it through the endothelial cells. It looks like that the endfeet of astrocytes, which do not form a real barrier, may regulate these cell junctions and influence the molecular traffic across the endothelial layer.
Figure 6. Drawing showing the main components of the blood-brain barrier: endothelium, basal lamina, pericytes and endfeet of astrocytes.
The term barrier is somehow misleading because it is not a strict barrier. There is an intense and selective exchange of molecules between the blood and the extracellular matrix of the nervous tissue. Even lymphocytes can cross it sometimes. Blood-brain barrier can be crossed by molecules with molecular weight under 500 kDa, liposoluble molecules and those that have a specific transporter. This selectivity may be a hurdle for some medicament to reach the neurons. It is curious that when some endothelial cell dies and the blood-brain barrier is compromised, oligodendroglia can patch the damaged region.
Astrocytes are resistant to low levels of oxygen and glucose. They can stay alive longer than neurons during deprivation times because they are able to store glycogen and produce ATP from anaerobic metabolic pathways. Thus, they are important during extreme situations and certain pathologies. After brain damages, astrocytes become reactive (reactive astrocytes) that leads to their hypertrophia or hyperplasia. This is called reactive gliosis. Two types of astrocytes can be distinguished during reactive gliosis. A2 astrocytes are mostly involved in repairing, whereas A1 astrocytes favor tissue degradation. A2 astrocytes are important for angiogenesis (formation of blood vessels). Reactive glia is observed in Parkinson, Alzheimer and Huntington chorea diseases. Furthermore, because they can divide, astrocytes are responsible for most brain tumors, known as glioma.
Astrocytes provide neurotrophic molecules to neurons, are a source of extracellular matrix, can act as detoxification centers; for example, they store some metals and ammonia.
Liddelow S, Barres B. 2015. SnapShot: Astrocytes in Health and Disease. Cell. 162: 1170-1170.e1.
Ransom B, Behar T, Nedergaard M. 2003. New roles for astrocytes (stars at last). Trends in neurosciences. 26: 520-522.
Tabata, H. 2015. Diverse subtypes of astrocytes and their development during corticogenesis. Frontiers in neurosciences. 9, 114.