Astrocytes

Location and Origin

Astrocytes are found exclusively in the CNS. There are two main types, the protoplasmic astrocytes found in gray matter surrounding neurons and the fibrous astrocytes located between axons in the white matter.
Astroglia originates from precursor cells of the neural tube, as the rest of the macroglia. Early in the development of the neural tube certain signaling factors provide macroglia precursor cells with the necessary information for them to migrate to specific areas of the forming brain and spinal cord. The process of signaling, migration and differentiation is similar to the corresponding for neurons with the latest research suggesting that the initial steps of the two processes are common and, in some cases, include the same precursor cells.

Structure

The astrocytes are large cells with branched processes extending away from the cell body. The cell's nucleus is large, round or ovoid, and lightly stained. The processes cannot be seen under the microscope with conventional stains but are clearly visible with gold or silver stains. The cytoskeleton of the cell body and the processes contains the glial fibrillary acidic protein (GFAP), an intermediate filament protein found almost exclusively in astrocytes. GFAP, along with other molecules, are used as markers for detecting astrocytes or classifying astrocyte-derived neoplasms.
The processes of astrocytes are characterized by a unique structure in the distal end, called astrocyte end-foot. This structure is equipped with specialized transmembrane proteins that enable direct interaction with other cellular or extracellular structures (basal laminae, glial or neuronal cellular membranes etc.) thereby allowing cell to cell signaling as well as adhesion to vessel walls.

The two astrocyte subtypes, protoplasmic and fibrous bear both morphological and functional differences:

• Protoplasmic astrocytes have many short processes with multiple branches extending towards all directions giving them the unique star-like appearance under a conventional microscope. Under an electron microscope protoplasmic astrocytes exhibit many organelles indicating high metabolic rates and a constant state of activation. Protoplasmic astrocytes are the most prevalent type.
• Fibrous astrocytes, compared to protoplasmic astrocytes, are equipped with fewer and longer processes that are lightly branched. They also have fewer organelles under electron microscope.

Apart from these two main types of astrocytes, numerous morphological variations have been described, including specialized cells in certain brain areas. These cells can be described as part of a wider astrocyte family due to great similarities with typical astrocytes in structure, function, and origin. Such cells are the Bergmann cells in the cerebellum.

Function and Physiology

Unlike the rest of the glia, the astrocytes do not perform only one major function and are rather involved in every physiological and pathophysiological pathway in the CNS. Their main functions are listed below:

• Participation in the formation of brain barriers. Astrocytes extend their processes to form a membrane that reinforces other structures in the brain and spinal cord. The most important structure that is fortified by astrocytic processes is the brain blood barrier (BBB). Blood vessels in the CNS initially enter the brain and spinal cord parenchyma accompanied by pia mater. As the vessels infiltrate deeper structures they branch and the pia mater surrounding them gradually becomes thinner. Finally at the level of capillaries the pia is no longer present. With the absence of the pia mater in this level there is a need for a barrier that restricts the passage of molecules from the blood to the nervous tissue. This restriction is essential due to the nerve cells' high susceptibility to even small concentration changes and toxic substances exposure. The astrocytes secure the BBB by the formation of a membrane around the vessel wall with the use of their processes. This membrane limits molecule passage, filters the blood and protects the nervous tissue from toxic exposure. As a result, on a transverse incision of a brain capillary it would be seen that the BBB is formed by the endothelium of the capillaries, the pericytes, the basement membrane, and the astrocyte end-feet or the vascular processes of the astrocytes, which in this case called astrocytic perivascular feet. Except for the BBB, another barrier consisting of the astrocytic end-feet is the one that separates the gray matter and other CNS areas from the pia mater. This barrier is called glial limiting membrane (glial limitans), and it mainly serves the purpose of isolating the nervous tissue from vascular and subarachnoid compartments. This membrane is formed by the pial processes of the astrocytes. 

• Regulation of substance concentration in the nervous tissue and nutrition of neurons. It is well known that the nervous tissue requires constant flow of nutrients due to the high metabolic rate of neurons and glial cells. By participating in the BBB astrocytes are the first to come in contact with macromolecules from the blood. Depending on the needs of nearby cells, an astrocyte delivers metabolites and other molecules to all other cells acting as a mediator. For example, blood derived cholesterol is firstly absorbed from an astrocyte and then distributed to nearby oligodendrocytes for myelination purposes. At the same time, astrocytes are equipped with ion pumps and gates on their membrane. This is due to their role of maintaining the necessary ion concentrations extracellularly. This is crucial for the formation of an ion gradient used for neuron action potentials. Astrocytes are particularly responsible for the perseverance of the desired concentration of extracellular K⁺. Furthermore, astrocytes channel toxic by-products through the BBB away from the nervous tissue therefore preventing neuronal damage.

• Support of neuronal development and neuroplasticity. At all the stages of the CNS development, astrocytes engage in the establishment of communication between neurons. Astrocyte processes, through signaling, guide the developing axons to the site of the synapse. The same mechanism of action is responsible for the involvement of the astroglia in neuronal plasticity in the adult CNS as well as axon repair and reconnection in the case of damage. Lastly, in addition to participating in the formation of the synapse an astrocyte is a part of the functioning synapse with the recycling and uptake of the neurotransmitters, the control of the pre- and post- synaptic cell metabolism and the up or downregulation of the synapse using signaling factors.

• Regulation of vessel constriction and dilation. An astrocyte can sense the metabolic rate of adjacent nerve cells and to subsequently signal blood vessels (through endothelial factors or changes in Ca²⁺ concentrations and other molecules called gliotransmitters) in order to cause vasodilation or vasoconstriction. Thus, the blood flow in different areas of the brain is regulated depending on which areas are more activated at the time, leading to maximum efficiency. The above phenomenon starts from a single cell but is amplified due to specialized gap junctions between astrocytes that allow them to collectively activate at the same time and give synchronized signals to nearby cells. This timed activation is a form of functional syncytium and is not only important for the regulation of blood flow in the CNS but expedites all the other functions of the astrocytes already mentioned.

• Synapse activation and neuronal communication. Recent research has uncovered that astrocytes actively engage in communication with neurons and release signaling molecules, known as gliotransmitters, to modulate interactions between neurons and between neurons and glial cells. The full extent of astroglial influence on nervous tissue organization and neuronal function is still being explored. For instance, the complexity of astrocytes is astonishing, with a single astrocyte's processes estimated to interact with millions of synapses.

• Response to damage. When stimulated, astrocytes transform into a more active form, called reactive astrocytes. This form mediates inflammatory responses, increases the BBB permeability, and activates neurotoxic factors that destroy damaged neurons. Astrocytes are a major part of the reaction generated by the nervous tissue in case of trauma or toxicity. Astrocytes form astrocytic scars in case of traumatic spinal cord or brain injury. Particularly in the event of acute ischemic damage, astrocytes appear swollen with a flat and peripherally positioned nucleus. These cells are called gemistocytes. Astrocytes also interact with microglia and present similar activation patterns in the case of pathogen invasion in the CNS. They mediate responses and organize the nervous tissue repair after the threat has been neutralized.

Learn more about astrocytes and other cells of the cerebral cortex in the following study unit: