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The subependymal layer in rodents: a site of structural plasticity and cell migration in the adult mammalian brain

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Abstract

The persistence of neurogenesis and structural plasticity was believed until recently to be restricted to lower vertebrates and songbirds. Nevertheless, it has now been ascertained that these phenomena can occur in the adult mammalian nervous system, at least in three distinct sites: the olfactory neuroepithelium of the nasal mucosa and two brain regions, namely, the hippocampal dentate gyrus and the olfactory bulb. The newly generated cells of the olfactory bulb originate from the subependymal layer, a remnant of the primitive subventricular zone persisting in the adult forebrain. Besides being characterized by high rates of cell proliferation, the subependymal layer is a site of long-distance tangential cell migration, wherein migrating cells form chains enwrapped by a particular type of astrocytes. These glial cells give rise to channels (glial tubes) that separate single chains from the surrounding mature tissue. The cellular composition and the pattern of cell migration in the mammalian subependymal layer appear to be quite different in neonatal and adult animals, changing strikingly in the postnatal period. Other features of uniqueness involve the capability of neuronal precursors to divide while undergoing migration and the presence of multipotent stem cells. Thus, the subependymal layer is an area of the adult mammalian brain endowed with a cohort of phenomena proper of neural development, persisting into (and adapted to) the fully mature nervous tissue. Such features make this system an optimal model to unravel mechanisms permitting highly dynamic structural plasticity during adulthood, in the perspective of providing strategies for possible brain repair.

Introduction

The tissue forming the brain or, more generally, the central nervous system (CNS) of higher vertebrates has been considered for a long time to be incapable of cell renewal during adulthood. Such a feature is explained by the fact that morphogenesis of the nervous tissue (neurogenesis), and the genesis of neurons in particular, follows a well-restricted spatial and temporal pattern. Neurogenesis mostly occurs in prenatal and early postnatal stages, within two relatively thin layers of tissue lining the primitive ventricular cavities, referred to as the ventricular zone and the subventricular zone [30]. From these actively proliferating zones, the newly generated cells usually migrate radially to reach newly formed layers in the intermediate zone, such as for example in the cerebral cortex 143, 145. As stated above, the temporal course of these processes is strictly regulated, although differences can be observed depending on the CNS regions and the animal species under study. In general, neurons are mostly formed prenatally whereas glial cells are prevalently generated after birth (for review, see [76]). Eventually, in mammals, the mitotically active layers disappear after birth along most of the neuraxis 3, 4, 158, leaving a mature nervous tissue that is considered largely static as concerns both the relationships among different cells and the potential for cell renewal.

Within the last three decades, a number of studies carried out in normal and lesioned animals indicated that structural plasticity can occur in certain areas of the adult mammalian nervous system. Such morphological plasticity can concern the shape of cells, involving changes in cell–cell contacts [170], or that of their processes, allowing a rearrangement of synapses [179]. More striking phenomena of structural plasticity imply the genesis of new cells, committed either to the neuronal or the glial lineage, which add to pre-existing cell populations or replace elements lost for several reasons. In the present article the attention will be focused on an area of the mammalian forebrain called the subependymal layer (SEL), representing a major source of newly generated cells during adulthood. A brief review on the other sites of active postnatal and adult neurogenesis will be provided, with the aim of underlining important differences in their potential for structural plasticity (see Table 1).

A delayed neurogenesis is known to occur in a transient cell layer (called the external granular layer) of the assembling cerebellar cortex, wherein actively mitotic cells generate the granule cells for the internal granular layer. This process, which involves a centripetal cell migration along fibers of persisting radial glial cells called Bergmann glia [144], is temporally restricted to the postnatal period (about 3 weeks in rodents 3, 76), and no cell proliferation or migration is detectable in the cerebellum of adult animals. Nevertheless, this delayed neurogenesis can be considered an exception to that occurring earlier in the embryonic subventricular zone, because the neurogenic layer is not in close contact with the ventricular cavity, reaching its peripheral position after a massive tangential migration from the wall of the fourth ventricle 5, 76.

True exceptions to the dogma of a temporal limit for neurogenesis have been described in three sites of the adult mammalian nervous system: the olfactory neuroepithelium, the hippocampus and the olfactory bulb (Table 1). The former is located outside the CNS, in the olfactory mucosa which lines the nasal cavities. The olfactory neuroepithelium is a relatively simple structure formed by undifferentiated basal cells (classified as globose and horizontal), non-neuronal supporting cells and olfactory receptor neurons. These latter neurons are continuously renewed, with a half-life ranging from 30 to 120 days, depending on the animal species 51, 66, 67, through differentiation of newly generated basal cells that are regarded as a unipotent stem cell compartment 35, 37. The olfactory receptor neurons represent an interesting model for the study of structural plasticity because they continuously send towards the olfactory bulb new axonal processes, which establish functional synapses with the dendrites of mitral, tufted and periglomerular cells 66, 67. However, the newly formed axonal projections enter the CNS only for a short distance, wherein they are enwrapped by a specialized type of glial cells permissive to axonal growth (ensheathing glia [147]). Moreover, the origin of the olfactory neuroepithelium from the olfactory placodes [52] implies a different process of neurogenesis in respect to that occurring in the CNS from the germinal layers that line the ventricular cavities. In addition, these receptors undergo cell renewal in an environment (the olfactory mucosa) that is not comparable with the mature brain nervous tissue.

Neurogenesis occurring within brain tissue has been described in the adult hippocampus and olfactory bulb. In the former, a certain rate of cell proliferation has been described in the dentate gyrus granular layer [6], giving rise to granule neurons 82, 92. In the rat, such neurogenesis has been observed up to 11 months of age [81]. Newly generated hippocampal granule cells extend dendrites and axons (mossy fibers); the latter grow through the hilus and the CA3 region of the Ammon’s horn [161], thus representing an example of long-distance axonal pathfinding through a mature brain neuropil. Unlike the olfactory receptor neurons, newly generated cells of the dentate gyrus substantially increase with age the existing neuronal population (about 40%), thus probably making available more postsynaptic sites during adulthood [15]. It has been proposed that hippocampal granule cells can originate during adulthood both from local proliferation in the granule cell layer and after short migration from the hilus 38, 92, in a manner similar to that described during postnatal development [155]. However, in spite of remarkable progress in the knowledge of the nature and potentialities of the progenitor cells in the hippocampus (reviewed in 57, 148), their origin and stemness properties still remain obscure.

The olfactory bulb is the other area of the mammalian CNS wherein neurogenesis has been described during adulthood 4, 14, 71, 72. In early studies this neurogenesis was already correlated with an adjacent region of the forebrain known as the SEL [30], a remnant of the primitive forebrain subventricular zone that persists during adulthood as an actively mitotic layer (see below). The SEL, which undoubtedly constitutes the major site of cell proliferation in the adult mammalian brain 4, 34, has been recently indicated as the source of cell precursors accounting for the olfactory bulb neurogenesis, after long-distance migration 104, 106. Thus, cell proliferation in the SEL and neurogenesis in the olfactory bulb are two extreme situations of a sole, complex system spanning the length of the forebrain (about 5–6 mm in rodents 4, 104). Recent studies carried out on this system provided evidence for several morphological and functional peculiarities, for example, the persistence of long-distance migration and multipotent stem cell compartment, which appear qualitatively and quantitatively different from those described in other neurogenetic areas of the adult mammalian nervous system (see Table 1).

The purpose of this article is to review the fine anatomy of the SEL and several aspects linked to the particular type of cell migration proper of this region, which make it an interesting model for studying persisting structural plasticity in the mammalian CNS.

Section snippets

Anatomy and terminology

During development, cells of the CNS originate from two deep layers characterized by active cell proliferation: the ventricular zone, directly lining the primitive ventricular cavities, and the subventricular zone, which originates later and is located beneath the former [30]. The ventricular zone contains the ultimate progenitors of CNS neurons and macroglial cells, then progressively transforms into the ependyma. The subventricular zone also generates neuronal and glial precursors, being

Concluding remarks

Studies carried out in the last decade have demonstrated that a continuous supply of newborn cells reaches the main and accessory olfactory bulb of rodents in the postnatal period and during adulthood. These cells are generated in the SEL, a strip of tissue characterized by intense proliferative activity, which also serves as a pathway for long-distance tangential migration. At present, many investigators agree that most of the newly generated cells reaching the olfactory bulb are neuronal

Acknowledgements

The authors thank Geneviéve Rougon for kindly providing the anti-PSA-NCAM antibody and Angelo Vescovi for stimulating discussion on stem cell biology. We also thank Elena Beltramo for her excellent technical help and photographic expertise. This work was supported by grants from the Ministero dell’Università e della Ricerca Scientifica e Tecnologica (MURST) and the Consiglio Nazionale delle Ricerche (CNR).

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    Present address: Department of Animal Biology, Via Accademia Albertina 13, I-10123 Turin, Italy.

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