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. It is the outermost layer of neural tissue, and among its responsibilities is the prevention of the over migration of neurons and neuroglia, the supporting cells of the nervous system, into the meninges. The glia limitans also plays an important role in regulating the movement of small molecules and cells into the brain parenchyma by working in concert with other components of the central nervous system (CNS) such as the blood–brain barrier (BBB). 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. It is the outermost layer of neural tissue, and among its responsibilities is the prevention of the over migration of neurons and neuroglia, the supporting cells of the nervous system, into the meninges. The glia limitans also plays an important role in regulating the movement of small molecules and cells into the brain parenchyma by working in concert with other components of the central nervous system (CNS) such as the blood–brain barrier (BBB). The perivascular feet of astrocytes form a close association with the basal lamina of the brain parenchyma to create the glia limitans. This membrane lies deep to the pia mater and the subpial space and surrounds the perivascular spaces (Virchow-Robin spaces). Any substance entering the central nervous system from the blood or cerebrospinal fluid (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. 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 that compose the vessel itself. These endothelial cells contain highly impermeable tight junctions that cause the blood vessels of the brain to exhibit none of the “leakiness” found in arteries and veins elsewhere in the body. Through both in vivo and in vitro 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 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. 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 junctions, it is not considered part of the BBB and material can readily pass between the foot processes. 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, complement proteins, cytokines, and chemokines. The astrocytes of the glia limitans are believed to be the component of the brain that secretes the pro- and anti-inflammatory factors. 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-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.