1. Neuronal Migration and Neurite Formation

In 1911, Ramon y Cajal perceived the functional importance of radial glia as directional guides for migrating immature nerve cells. The concept of glial guidance first described by Rakic in 1971, and derived from the observation of a tight association between migrating granule cells and Bergmann fibers in the developing molecular layer of the cerebellum, underlies a commonly used mechanism for the positioning of young postmitotic neurons in developing brain. Neuronal migration is a key step in neural morphogenesis since inadequately located neurons may not establish the appropriate connections, and this may lead to neuronal death or to functional deficits of synaptic circuits. The close structural relationship between radial glia and migrating neurons consist in a radial unit. Radial glial fibers are present in large numbers during peak periods of neuronal cell migration in each structure of the developing primate nervous system. During the entire period of cell migration to the neocortex, a single radial process can guide several hundreds of neurons that originated from the same position in the ventricular zone, the so-called proliferative unit. Although the migrating neuron encounters myriad processes in various orientations, it remains constantly apposed to radially oriented fibers. Thus, there is a vertical columnar organization of the brain. From counts on samples of ventricular zones, it has been determined that the total number of ontoge-netic columns is several millions. The remarkable expansion of the cortical surface during evolution can be explained by an increase in the number of prolif-erative units, as a single round of cell division doubles the number of ontogenetic columns and therefore the number of cells in the cortex. Within each column, neurons generated earlier occupy deeper positions; therefore, those arriving later have to pass them, along the glial radial fiber, to become situated more superficially. This constitutes an "inside-out" sequence of time of origin of neurons in the cerebral isocortex. There is a neuronal leading process along the glial guide, and the neuronal cell body is the site of adhesion of the migrating neuron.

Neuronal cell migration requires the cooperative interaction of adhesion and recognition molecules, which may be expressed by neurons and radial glial cells. Migratory granule neural cells in the cerebellum produce a cell adhesion molecule, astrotactin, that enables them to ride the glial scaffold. The blockage of astrotactin curtails neuronal migration in vitro. Although at this stage some of the numerous molecules involved in neuronal migration have been identified, the exact mechanisms involved in the selection of a pathway, migration, and departing from this pathway remain obscure.

In the adult mammalian forebrain, neuronal precursors born in the SVZ of the neonatal and adult rodent brain are able to migrate 3-8 mm from the walls of the lateral ventricle into the olfactory bulb, where they differentiate into olfactory interneurons. This migration depends on a persistent manifestation of the RMS that was first reported in the developing rodent brain. This tangentially oriented migration occurs without the guidance of radial glial or axonal processes. The cells are closely associated, forming elongated aggregates called "migration chains'' that are ensheathed and moved within channels formed by the processes of specialized astrocytes. However, the role of these astrocytic tunnels is unclear. If the migration of neuroblasts by chain migration is a glial-independent movement, these glial cells may provide in vivo a permissive environment and directional cues for migration to the olfactory bulb, restricting the dispersal of neuroblasts outside the migratory stream or isolating the migrating cells from the surrounding parenchyma.

Neurons have the intrinsic property of generating two distinct sets of processes, one axon and multiple dendrites. Some of the mechanisms underlying polarized sorting of membrane and cytosolic proteins are similar in neurons and other polarized cells, such as epithelial cells. The axonal membrane of neurons shares properties with the apical membrane domain of epithelial cells, whereas the soma and the dendritic arbor of neurons corresponds to the basolateral domain of epithelial cells. Glial cells can control neuronal shape. It was recently shown in culture that the dendritic branching of GABAergic neurons requires signaling from living astrocytes. Among several mechanisms, neurite outgrowth can be promoted by regulating the degradation of the extracellular matrix by protease inhibitors, such as the glia-derived nexin.

2. Astrocyte Boundaries and Neural Pathways

Throughout neurogenesis, the diverse neural cell populations have to establish their correct pathways to find their proper locations and establish correct connections with neural partners. Moreover, the formation of the adult architecture of neuronal networks is essentially based on directed neurite extension. Growth cones have to find their way to their target region by crossing permissive substrates and diffusible factors and avoiding repulsive ones. Glial cells have been proposed to provide some pathways for axon growth in mammalian brain. Therefore, interactions with molecules secreted in the extracellular matrix by glial cells have been implicated in the formation of boundaries separating anatomically defined regions in the CNS. Within the developing nervous system, such boundaries are present in numerous regions of the CNS, such as the diencepha-lic/telencephalic junction, the optic chiasm, the mid-line of the developing forebrain, and the cerebral commissures. Among the components of the extracellular matrix, many are synthesized during development by glial cells such as tenascin-C and -R, thrombospondin-1, and laminin as well as a variety of proteoglycans; these molecules can act as either promoters or inhibitors of neural cell migration and neurite outgrowth. When functional patterns have formed and appear to be stabilized, these boundaries are no longer detectable, but can be reexpressed in reaction to injury. Astroglial maturation is accompanied by a decrease in expression of molecules such as laminin, NCAM, L1, and heparan sulfate proteogly-can, which are known to promote axonal outgrowth. In parallel, the maturation of astrocytes is accompanied by an increase in the synthesis ofmolecules known to inhibit neurite outgrowth, such as chondroitin sulfate proteoglycan and tenascin.

Adult Dyslexia

Adult Dyslexia

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