The glia limitans, or the glial limiting membrane, is a thin barrier of

astrocyte Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of endo ...

foot processes associated with the

parenchymal Parenchyma () is the bulk of functional substance in an animal organ or structure such as a tumour. In zoology it is the name for the tissue that fills the interior of flatworms. Etymology The term ''parenchyma'' is New Latin from the word ...

basal lamina The basal lamina is a layer of extracellular matrix secreted by the epithelial cells, on which the epithelium sits. It is often incorrectly referred to as the basement membrane, though it does constitute a portion of the basement membrane. The ba ...

surrounding the

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...

and

spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the spi ...

. It is the outermost layer of

neural tissue Nervous tissue, also called neural tissue, is the main tissue (biology), tissue component of the nervous system. The nervous system regulates and controls body functions and activity. It consists of two parts: the central nervous system (CNS) com ...

, and among its responsibilities is the prevention of the over-migration of

neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...

s and

neuroglia Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses. They maintain homeostasis, form mye ...

, the supporting cells of the nervous system, into the

meninges In anatomy, the meninges (, ''singular:'' meninx ( or ), ) are the three membranes that envelop the brain and spinal cord. In mammals, the meninges are the dura mater, the arachnoid mater, and the pia mater. Cerebrospinal fluid is located in th ...

. The glia limitans also plays an important role in regulating the movement of small molecules and cells into the

brain tissue The human brain is the central organ of the human nervous system, and with the spinal cord makes up the central nervous system. The brain consists of the cerebrum, the brainstem and the cerebellum. It controls most of the activities of the ...

by working in concert with other components of the central nervous system (CNS) such as the blood–brain barrier (BBB).

Location and structure

The perivascular feet of

s form a close association with the basal lamina of the

brain parenchyma Parenchyma () is the bulk of functional substance in an animal organ or structure such as a tumour. In zoology it is the name for the tissue that fills the interior of flatworms. Etymology The term ''parenchyma'' is New Latin from the word � ...

to create the glia limitans. This membrane lies deep to the

pia mater Pia mater ( or ),Entry "pia mater"
in
subpial space and surrounds the

perivascular space A perivascular space, also known as a Virchow–Robin space, is a fluid-filled space surrounding certain blood vessels in several organs, including the brain, potentially having an immunological function, but more broadly a dispersive role fo ...

s (Virchow-Robin spaces). Any substance entering the central nervous system from the blood or

cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the bra ...

(CSF) must cross the glia limitans. The two different classifications of glial limiting membrane, the glia limitans perivascularis and the glia limitans superficialis, have nearly identical structures, however, they can be distinguished from each other by their location within the brain. The glia limitans perivascularis abuts the perivascular space surrounding the parenchymal blood vessels and functions as a supportive constituent of the blood–brain barrier. In contrast, the non-parenchymal blood vessels present in the subarachnoid space are not covered by the glia limitans. Instead, the entire subarachnoid space is sealed towards the nervous tissue by the glia limitans superficialis. These two parts of the glia limitans are continuous; however, convention dictates that the part that covers the surface of the brain is referred to as the superficialis, and the part that encloses the blood vessels within the brain is called the perivascularis.

Function

Physical barrier

Glial distribution of Cu Zn SOD immunoreactivity in rat glia limitans

The main role of the glia limitans is to act as a physical barrier against unwanted cells or molecules attempting to enter the CNS. The glia limitans compartmentalizes the brain to insulate the parenchyma from the vascular and subarachnoid compartments. Within the brain, the glial limiting membrane is an important constituent of the blood–brain barrier. Experiments using electron-dense markers have discovered that functional components of the blood–brain barrier are the

endothelial cells The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...

that compose the vessel itself. These endothelial cells contain highly impermeable

tight junction Tight junctions, also known as occluding junctions or ''zonulae occludentes'' (singular, ''zonula occludens''), are multiprotein junctional complexes whose canonical function is to prevent leakage of solutes and water and seals between the epith ...

s that cause the blood vessels of the brain to exhibit none of the “leakiness” found in

arteries An artery (plural arteries) () is a blood vessel in humans and most animals that takes blood away from the heart to one or more parts of the body (tissues, lungs, brain etc.). Most arteries carry oxygenated blood; the two exceptions are the pul ...

and

vein Veins are blood vessels in humans and most other animals that carry blood towards the heart. Most veins carry deoxygenated blood from the tissues back to the heart; exceptions are the pulmonary and umbilical veins, both of which carry oxygenated b ...

s elsewhere in the body. Through both

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

and

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...

experiments the astrocytic foot processes of the glia limitans were shown to induce the formation of the tight junctions of the endothelial cells during brain development. The in vivo experiment involved harvested rat astrocytes that were placed into the anterior chamber of a chick-eye or on the chorioallantois. Permeable blood vessels from either the

iris Iris most often refers to: *Iris (anatomy), part of the eye *Iris (mythology), a Greek goddess * ''Iris'' (plant), a genus of flowering plants * Iris (color), an ambiguous color term Iris or IRIS may also refer to: Arts and media Fictional ent ...

or chorioallantois became impermeable to blue-albumin once they had entered the transplanted bolus of astrocytes. In the in vitro experiment, endothelial cells were first cultured alone and the

tight junctions Tight junctions, also known as occluding junctions or ''zonulae occludentes'' (singular, ''zonula occludens''), are multiprotein junctional complexes whose canonical function is to prevent leakage of solutes and water and seals between the epith ...

were observed in freeze-fracture replicas to be discontinuous and riddled with

gap junctions Gap junctions are specialized intercellular connections between a multitude of animal cell-types. They directly connect the cytoplasm of two cells, which allows various molecules, ions and electrical impulses to directly pass through a regulate ...

. Then, the brain endothelial cells were cultured with astroctytes resulting in enhanced tight junctions and a reduced frequency of gap junctions. The glia limitans also acts as a second line of defense against anything that passes the blood–brain barrier. However, because the astrocytes surrounding the vessels are connected by

gap junction Gap junctions are specialized intercellular connections between a multitude of animal cell-types. They directly connect the cytoplasm of two cells, which allows various molecules, ions and electrical impulses to directly pass through a regulate ...

s, it is not considered part of the BBB and material can readily pass between the foot processes.

Immunological barrier

The astrocytes of the glia limitans are responsible for separating the brain into two primary compartments. The first compartment is the immune-privileged brain and spinal cord parenchyma. This compartment contains multiple immunosuppressive cell surface proteins such as CD200 and CD95L and it allows for the release of anti-inflammatory factors. The second compartment is that of the non-immune-privileged subarachnoid, subpial, and perivascular spaces. This area is filled with pro-inflammatory factors such as

antibodies An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...

complement proteins The complement system, also known as complement cascade, is a part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and a ...

cytokines Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...

, and

chemokines Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addition ...

. The astrocytes of the glia limitans are believed to be the component of the brain that secretes the

pro- This is a list of common affixes used when scientifically naming species, particularly extinct species for whom only their scientific names are used, along with their derivations. *a-, an-: ''Pronunciation'': /ə/, /a/, /ən/, /an/. ''Origin'' ...

and

anti-inflammatory Anti-inflammatory is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs remedy pain by reducing inflammation as o ...

factors.

Development

The development of the long astrocyte cellular processes that are integral to the glia limitans structure has been linked to the presence of meningeal cells in the pia mater. Meningeal cells are specialized

fibroblast A fibroblast is a type of cell (biology), biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and plays a critical role in wound ...

-like cells that surround the CNS and major blood vessels. They have been found to co-operate with astrocytes in the initial formation of the glia limitans during development and participate in its continued maintenance throughout life. Artificially induced destruction of meningeal cells during CNS development have been found to result in the alteration of subpial extracellular matrix and a disruption of the glia limitans. The glia limitans has also proven to be important in the recovery of the CNS after injuries. When lesions are made on the brain surface, meningeal cells will divide and migrate into the lesion, eventually lining the entire injury cavity. If the injury has significantly reduced the density of astrocytes and created space within the tissue, the meningeal cells will invade even more diffusely. As invading meningeal cells make contact with astrocytes, they can induce the formation of a new, functional glia limitans. The new glia limitans formed after CNS injury usually presents itself as a barrier to regenerating axons.

Clinical relevance

There are a number of diseases associated with problems or abnormalities with the glia limitans. Many diseases can arise from a breach to the glia limitans in which it will no longer be able to fulfill its functional role as a barrier. Two of the more common diseases resulting from a breach to the glia limitans are described below.

Fukuyama-type congenital muscular dystrophy (FCMD)

Breaches in the glia limitans-basal lamina complex have been associated with Fukuyama-type congenital muscular dystrophy (FCMD), which is thought to be the result of micropolygyri, or small protrusions of nervous tissue. Although the underlying mechanism for the formation of these breaches is largely unknown, recent research has indicated that the protein

fukutin Fukutin is a eukaryotic protein necessary for the maintenance of muscle integrity, cortical histogenesis, and normal ocular development. Mutations in the fukutin gene have been shown to result in Fukuyama congenital muscular dystrophy (FCMD) ...

is directly linked to the developing lesions. Mutations in the fukutin protein lead to a depressed level of its expression in the brain and spinal cord of neonatal subjects, which in turn has been found to contribute to the weakening of the structural integrity of the glia limitans. Neuronal and glial cells migrate through the weakened barrier resulting in the accumulation of neural tissue in the subarachnoid space. This abnormal migration, known as

cortical dysplasia Focal cortical dysplasia (FCD) is a congenital abnormality of brain development where the neurons in an area of the brain failed to migrate in the proper formation in utero. ''Focal'' means that it is limited to a focal zone in any lobe. Focal co ...

, is theorized to be one of the primary causes for FCMD.

Experimental autoimmune encephalomyelitis (EAE)

It has been demonstrated that the clinical signs of

experimental autoimmune encephalomyelitis Experimental autoimmune encephalomyelitis, sometimes experimental allergic encephalomyelitis (EAE), is an animal model of brain inflammation. It is an inflammatory demyelinating disease of the central nervous system (CNS). It is mostly used with r ...

(EAE) are only evident after the penetration of inflammatory cells across the glia limitans and upon entrance into the CNS parenchyma. The activity of matrix

metalloproteinases A metalloproteinase, or metalloprotease, is any protease enzyme whose catalytic mechanism involves a metal. An example is ADAM12 which plays a significant role in the fusion of muscle cells during embryo development, in a process known as myoge ...

, specifically MMP-2 and MMP-9, are required for the penetration of the glia limitans by inflammatory cells. This is most likely due to the biochemistry of the parenchymal basement membrane and the astrocytic foot processes. MMP-2 and MMP-9 are both produced by

myeloid cells A myelocyte is a young cell of the granulocytic series, occurring normally in bone marrow (can be found in circulating blood when caused by certain diseases). Structure When stained with the usual dyes, the cytoplasm is distinctly basophilic ...

, which surround

T cells A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell re ...

in the perivascular space. These metalloproteinases allow immune cells to breach the glia limitans and reach the CNS parenchyma to attack the CNS parenchymal cells. Once the immune cells have reached the CNS parenchyma and the immune attack is underway, the CNS parenchymal cells are sacrificed in order to battle the infection. The autoimmune response to EAE leads to chronic attack of

oligodendrocytes Oligodendrocytes (), or oligodendroglia, are a type of neuroglia whose main functions are to provide support and insulation to axons in the central nervous system of jawed vertebrates, equivalent to the function performed by Schwann cells in the p ...

and neurons, which promotes

demyelination A demyelinating disease is any disease of the nervous system in which the myelin sheath of neurons is damaged. This damage impairs the conduction of signals in the affected nerves. In turn, the reduction in conduction ability causes deficiency i ...

and axonal loss. This can ultimately result in the loss of CNS neurons.

Comparative anatomy

Because the glia limitans serves such an important structural and physiological function in human beings, it is unsurprising that evolutionary precursors of the glial limiting membrane can be found in many other animals.

Insect Insects (from Latin ') are pancrustacean hexapod invertebrates of the class Insecta. They are the largest group within the arthropod phylum. Insects have a chitinous exoskeleton, a three-part body ( head, thorax and abdomen), three pairs ...

s have an

open circulatory system The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...

, so there are no blood vessels found within their

ganglia A ganglion is a group of neuron cell bodies in the peripheral nervous system. In the somatic nervous system this includes dorsal root ganglia and trigeminal ganglia among a few others. In the autonomic nervous system there are both sympatheti ...

. However, they do have a sheath of perineurial glial cells that envelops the nervous system and exhibit the same tight occluding junctions that are induced by the glia limitans in humans. These cells act as a barrier and are responsible for establishing permeability gradients. In certain

molluscs Mollusca is the second-largest phylum of invertebrate animals after the Arthropoda, the members of which are known as molluscs or mollusks (). Around 85,000 extant taxon, extant species of molluscs are recognized. The number of fossil sp ...

, a glial-interstitial fluid barrier is observed without the presence of tight junctions.

Cephalopod A cephalopod is any member of the molluscan class Cephalopoda (Greek plural , ; "head-feet") such as a squid, octopus, cuttlefish, or nautilus. These exclusively marine animals are characterized by bilateral body symmetry, a prominent head ...

molluscs, in particular, have cerebral ganglia that have

microcirculation The microcirculation is the circulation of the blood in the smallest blood vessels, the microvessels of the microvasculature present within organ tissues. The microvessels include terminal arterioles, metarterioles, capillaries, and venules. ...

, often seen in the composition of higher organisms. Often, the glial cells will form a seamless sheath completely around the blood space. The barrier consists of zonular intercellular junctions, rather than tight junctions, with clefts formed by extracellular

fibril Fibrils (from the Latin ''fibra'') are structural biological materials found in nearly all living organisms. Not to be confused with fibers or filaments, fibrils tend to have diameters ranging from 10-100 nanometers (whereas fibers are micro ...

s. In addition to protection from the blood, these barriers are thought to exhibit local control of the microenvironment around specific neuron groups, a function required for complex nervous systems. Monkeys and other primates have been found to have a glial limiting membrane extremely similar to humans. Studies on these animals have revealed that the thickness of the glia limitans not only varies greatly among different species, but also within different regions of the central nervous system of the same organism. Further observations of young and old

monkey Monkey is a common name that may refer to most mammals of the infraorder Simiiformes, also known as the simians. Traditionally, all animals in the group now known as simians are counted as monkeys except the apes, which constitutes an incomple ...

s have proven that the younger subjects have thinner membranes with fewer layers of astrocytic processes while the older monkeys possess much thicker membranes.

Current research

As of 2011, research is focused on the two-way communication between neurons and glial cells. Communication between these two types of cells allows for axonal conduction, synaptic transmission, as well as the processing of information to regulate and better control the processes of the central nervous system. The various forms of communication include

neurotransmission Neurotransmission (Latin: ''transmissio'' "passage, crossing" from ''transmittere'' "send, let through") is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron (the presynaptic neuron), ...

, ion fluxes and

signaling molecules In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellula ...

. As recently as 2002, new information on the process of neuron-glia communication was published by R. Douglas Fields and Beth Stevens-Graham. They used advanced imaging methods to explain that the

ion channel Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of io ...

s seen in glial cells did not contribute to

action potential An action potential occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells, ...

s but rather allowed the glia to determine the level of neuronal activity within proximity. Glial cells were determined to communicate with one another solely with chemical signals and even had specialized glial-glial and neuron-glial neurotransmitter signaling systems. Additionally, neurons were found to release chemical messengers in extrasynaptic regions, suggesting that the neuron-glial relationship includes functions beyond synaptic transmission. Glia have been known to assist in

synapse In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell. Synapses are essential to the transmission of nervous impulses from ...

formation, regulating synapse strength, and information processing as mentioned above. The process for

adenosine triphosphate Adenosine triphosphate (ATP) is an organic compound that provides energy to drive many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all known forms of ...

(ATP),

glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...

, and other chemical messenger release from glia is debated and is seen as a direction for future research.

References

{{Use dmy dates, date=April 2017 Glial cells Cellular neuroscience