User:Katie44gb/Glia Limitans

The glia limitans, or the glial limiting membrane, is a thin barrier of astrocyte foot processes associated with the parenchymal basal lamina surrounding the brain and spinal cord. The glia limitans is the outermost layer of neural tissue and is responsible for preventing the over migration of neurons and  glial cells out of the  central nervous system (CNS). The glia limitans also plays an important role in the regulation of the movement of small molecules into the parenchyma and works in concert with other components of the brain including the blood brain barrier (BBB).

Location and Structure
The end foot processes extending from both perivascular and marginal astrocytes form a close association with the basal lamina of the parenchyma to create the glia limitans. This membrane lies deep to the pia mater and the subpial space and surrounds the perivascular (Virchow-Robin) space. Any cell entering the CNS parenchyma from the blood or cerebrospinal fluid (CSF) must cross the glia limitans.

The two different types of glial limiting membrane, the glia limitans perivascularis and the glia limitans superficialis, can be distinguished from each other by their location in the brain. However, the structures of both the glia limitans superficialis and perivascularis are nearly identical. The glia limitans perivascularis abuts the perivascular space surrounding the parenchymal blood vessels. The cerebrospinal fluid within the perivascular space drains into the subarachnoid space. The meningeal blood vessels present in the subarachnoid space are not covered by the glia limitans, instead the entire subarachnoid space is sealed towards the neuropil by the glia limitans superficialis.

Physical Barrier
The glial limitans main function is structural, functioning as a physical barrier. The glia limitans compartmentalizes the brain to insulate the parenchyma from the vascular and subarachnoid compartments. Glial cells communicate with other glia cells via calcium and intercellular diffusion of chemical messengers, allowing a large number of glial cells to coordinate activity and act in a uniform manner.

Immunological Barrier
The astrocytes of the glia limitans are responsible for separating two compartments of the brain in regard to the microenvironment. The first compartment is the immune-privileged brain and spinal cord parenchyma. This compartment contains multiple immune suppressive 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, complement, cytokines, and chemokines. Therefore, the glia limitans is not only a tissue barrier because the astrocytes associated with it secret pro- and anti-inflammatory factors. These factors allow the glia limitans to act as an immunological barrier

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. Although the underlying mechanism for the formation of these breaches in the glia limitans is largely unknown, recent research has indicated that the protein fukutin is directly linked to the developing lesions. Mutations in the fukutin protein lead to a depressed level of 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. Neural and glial tissues migrate through the breach resulting in the accumulation of neural tissue in the subarachnoid space. The resulting cortical dysplasia is theorized to be one of the primary causes for FCMD.

Experimental Autoimmune Encephalomyelitis (EAE)
It has been demonstrated that clinical signs of Experimental autoimmune encephalomyelitis (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, specifically MMP-2 and MMP-9, is 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, which surround T cells 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 and neurons, which promotes demyelination and axonal loss. This can ultimately result in the loss of CNS neurons.

Development


Through in vivo and in vitro experiments, astroglial cells were linked to glial limiting membrane 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 vessels from either the iris 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 were observed in freeze-fracture replicas to be discontinuous and riddled with gap junctions. Then, the brain endothelial cells were cultured with astroctytes resulting in enhanced tight junctions and a reduced frequency of gap junctions. As a control, cells other than astrocytes were individually cultured with the edothelial cells and no enhancement of the tight junctions was observed. From the combination of experiments, it is deduced that astrocytes are essential to the development of the glia limitans.

Meningeal and glial cells are thought to induce astrocytes to develop long cellular processes. Meningeal cells are specialized fibroblast-like cells that surround the CNS and major blood vessels. Meningeal cells co-operate with astrocytes in the formation of the glia limitans. After CNS injuries, meningeal cells will divide and migrate into the injury cavity. Here they will line the entire injury cavity and if the injury has reduced the density of astrocytes and created space within the tissue, the meningeal cells will invade more diffusely. As invading meningeal cells make contact with astrocytes, they can lead to the formation of a new glia limitans. The new glia limitans formed after CNS injury usually presents itself as a barrier to regenerating axons. It is clear that meningeal cells are important in the formation and maintenance of the glia limitans because 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.

Comparative Anatomy
Insects do not have blood vessels within their ganglia, but rather a sheath of perineurial glial cells that envelope the nervous system with occluding tight junctions These cells act as a barrier and are responsible for establishing permeability gradients.

In certain molluscs, a glial-interstitial fluid barrier is observed without the presence of tight junctions. Cephalopod molluscs in particular have cerebral ganglia that have microvessels, 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 fibrils. 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.

The thickness of the glial limiting membrane not only varies greatly among different species but also within different regions of the central nervous system of the same organism. Observations of young and old monkeys have proven that the younger subjects have thinner membranes with fewer layers of astrocytic processes while the older monkeys possess much thicker membranes.

Relationship with Blood Brain Barrier
Astrocytic foot processes not only form the glia limitans but they also provide the base structure for the relationship between astroctyes and the blood brain barrier. The endfeet of astrocytes do form a complete layer, however the junctions between the astrocytes are gap junctions. As a result substances can pass between through the endothelial cells. Using electron-dense markers, it has been discovered that the blood brain barrier rests at the level of the endothelial cells, solving this problem by providing a physical barrier and allowing for selective transport.

Current Research
Current 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, ion fluxes and signaling molecules. 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 channels seen in glial cells did not contribute to action potentials 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 formation, regulating synapse strength, and information processing as mentioned above. The process for ATP, glutamate, and other chemical messenger release from glia is debated and is seen as a direction for future research.