Glial cells were long considered end products of neural differentiation, specialized supportive cells with an origin very different from that of neurons. New studies have shown that some glial cells—radial glia (RG) in development and specific subpopulations of astrocytes in adult mammals—function as primary progenitors or neural stem cells (NSCs). This is a fundamental departure from classical views separating neuronal and glial lineages early in development. Direct visualization of the behavior of NSCs and lineage-tracing studies reveal how neuronal lineages emerge. In development and in the adult brain, many neurons and glial cells are not the direct progeny of NSCs, but instead originate from transit amplifying, or intermediate, progenitor cells (IPCs). Within NSCs and IPCs, genetic programs unfold for generating the extraordinary diversity of cell types in the central nervous system. The timing in development and location of NSCs, a property tightly linked to their neuroepithelial origin, appear to be the key determinants of the types of neurons generated. Identification of NSCs and IPCs is critical to understand brain development and adult neurogenesis and to develop new strategies for brain repair.

The glial nature of embryonic and adult neural stem cells

Degeneration and regeneration of the nervous system

The brain is a singular organ of unique biological complexity that serves as the command center for cognitive and motor function. As such, this specialized system also possesses a unique chemical composition and reactivity at the molecular level. In this regard, two vital distinguishing features of the brain are its requirements for the highest concentrations of metal ions in the body and the highest per-weight consumption of body oxygen. In humans, the brain accounts for only 2% of total body mass but consumes 20% of the oxygen that is taken in through respiration. As a consequence of high oxygen demand and cell complexity, distinctly high metal levels pervade all regions of the brain and central nervous system. Structural roles for metal ions in the brain and the body include the stabilization of biomolecules in static (e.g., Mg2+ for nucleic acid folds, Zn2+ in zinc-finger transcription factors) or dynamic (e.g., Na+ and K+ in ion channels, Ca2+ in neuronal cell signaling) modes, and catalytic roles for brain metal ions are also numerous and often of special demand.

Metals in Neurobiology: Probing Their Chemistry and Biology with Molecular Imaging

Despite a hundred years' research, the neuropathology of schizophrenia remains obscure. However, neither can the null hypothesis be sustained--that it is a 'functional' psychosis, a disorder with no structural basis. A number of abnormalities have been identified and confirmed by meta-analysis, including ventricular enlargement and decreased cerebral (cortical and hippocampal) volume. These are characteristic of schizophrenia as a whole, rather than being restricted to a subtype, and are present in first-episode, unmedicated patients. There is considerable evidence for preferential involvement of the temporal lobe and moderate evidence for an alteration in normal cerebral asymmetries. There are several candidates for the histological and molecular correlates of the macroscopic features. The probable proximal explanation for decreased cortical volume is reduced neuropil and neuronal size, rather than a loss of neurons. These morphometric changes are in turn suggestive of alterations in synaptic, dendritic and axonal organization, a view supported by immunocytochemical and ultrastructural findings. Pathology in subcortical structures is not well established, apart from dorsal thalamic nuclei, which are smaller and contain fewer neurons. Other cytoarchitectural features of schizophrenia which are often discussed, notably entorhinal cortex heterotopias and hippocampal neuronal disarray, remain to be confirmed. The phenotype of the affected neuronal and synaptic populations is uncertain. A case can be made for impairment of hippocampal and corticocortical excitatory pathways, but in general the relationship between neurochemical findings (which centre upon dopamine, 5-hydroxytryptamine, glutamate and GABA systems) and the neuropathology of schizophrenia is unclear. Gliosis is not an intrinsic feature; its absence supports, but does not prove, the prevailing hypothesis that schizophrenia is a disorder of prenatal neurodevelopment. The cognitive impairment which frequently accompanies schizophrenia is not due to Alzheimer's disease or any other recognized neurodegenerative disorder. Its basis is unknown. Functional imaging data indicate that the pathophysiology of schizophrenia reflects aberrant activity in, and integration of, the components of distributed circuits involving the prefrontal cortex, hippocampus and certain subcortical structures. It is hypothesized that the neuropathological features represent the anatomical substrate of these functional abnormalities in neural connectivity. Investigation of this proposal is a goal of current neuropathological studies, which must also seek (i) to establish which of the recent histological findings are robust and cardinal, and (ii) to define the relationship of the pathological phenotype with the clinical syndrome, its neurochemistry and its pathogenesis.

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The neuropathology of schizophrenia. A critical review of the data and their interpretation.

Molecular profile of reactive astrocytes—Implications for their role in neurologic disease

Nerve endings from rat brain tissue release copper upon depolarization. A possible role in regulating neuronal excitability.

The topographical mapping of glial fibrillary acidic protein (GFAP)-immunoreactivity was performed in coronal serial sections of the rat mesencephalon, rhombencephalon and spinal cord. Relative to a background of poor or moderate overall staining of the mesencephalon, the interpeduncular nucleus, substantia nigra and the periaqueductal grey matter were prominent by their intense GFAP-immunoreactivity. The pons and particularly the medulla contained more GFAP-labelled elements compared with the mesencephalon. The spinal trigeminal nucleus and Rolando substance were distinguished by their intense staining. Large fibre tracts were usually poor in immunoreactive GFAP. In a concluding discussion, findings relevant to the GFAP-mapping of the whole rat CNS are evaluated with regard to possible reasons underlying the observed differential distribution of GFAP-immunoreactivity.

Distribution of glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes in the rat brain. II. Mesencephalon, rhombencephalon and spinal cord.

In the first of two papers dealing with the distribution of glial fibrillary acidic protein-(GFAP)-immunoreactive elements in the rat brain, the localization of immunostaining in the forebrain is systematically described. While the limbic cortex was found to contain intensely stained, evenly distributed astrocytes, the neocortex showed clearly stratified GFAP-staining, with substantially less immunoreactivity occurring in the middle layers than in the areas close to the brain surface or the white matter. A remarkably regular staining pattern was observed in the hippocampus and dentate gyrus. The striatum remained unstained in sharp contrast to the pallidum. In the diencephalon, the main thalamic nuclei were poor in GFAP-labelled elements in contrast to the internuclear border zones. In the hypothalamus, nuclei were conspicuous by their GFAP-staining. A consistent differential staining pattern was obtained in the epithalamic structures. The observed distributional pattern of diencephalic GFAP-immunoreactivity is thought to be due to different regional proliferation of the embryonic neuroepithelium of the diencephalon. The uneven distribution of GFAP-immunoreactivity in the forebrain is explained on a mainly developmental basis.

Distribution of glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes in the rat brain. I. Forebrain.

The present paper is the first comprehensive study on the astroglia of a teleost fish that is based on the immunohistochemical staining of GFAP (glial fibrillary acidic protein, an immunohistochemical marker of astroglia). The ray-finned fishes (Actinopterygii) and their largest group, the Teleostei, represent a separate pathway of vertebrate evolution. Their brain has a very complex macroscopic structure; several parts either have no equivalents in tetrapods or have a very different shape, e.g., the telencephalon. The results show that the teleost brain has a varied and highly specialized astroglial architecture. The primary system is made up of radial glia, which are of ependymal origin and cover the pial surface with endfeet. The tendency is, however, that the more caudal a brain area is, the less regular is the radial arrangement. A typical radial glia dominates some parts of the diencephalon (median eminence, lobus inferior and habenula) and the telencephalon. In the rest of the diencephalon and in the mesencephalon, the course of the glial fibers is modified by brain tracts. The most specialized areas of the teleost brain, the optic tectum and the cerebellum, display elaborate variations of the original radial system, which is adapted to their layered organization. In the cerebellum, an equivalent of the Bergmannglia can be found, although its fiber arrangement shows meaningful differences from that of mammals or birds. In the lower brain stem radial glia are confined to fibers separating the brain tracts and forming the midline raphe. A dense ependymoglial plexus covers the inner surface of the tectum and the bottom of the rhombencephalic ventricle, intruding into the vagal and facial lobes. The structure and the position of the rhombencephalic plexus suggest that it corresponds to a circumventricular organ that entirely occupies the bottom of the ventricle. Perivascular glia show an unusual form as they consist of long fibers running along the blood vessels. In the large brain tracts long glial fibers run parallel with the course of the neural fibers. At least in the diencephalon, these glial fibers seem to be modified radial fibers. Real astrocytes (i.e., stellate-shaped cells) can be found only in the brain stem and even there only rarely. The glial specialization in the various areas of the teleost brain seems to be more elaborate than that found either in amphibia or in reptiles.

Astroglial architecture of the carp (Cyprinus carpio) brain as revealed by immunohistochemical staining against glial fibrillary acidic protein (GFAP)

Computer-assisted image analysis was used to map the regional distribution of glial fibrillary acidic protein-immunoreactive (GFAP-IR) astrocytes in the rat forebrain, and mesencephalon. A complete survey of packing densities of GFAP-IR structures was performed. Computer maps revealed high values in the outer and inner layers of the cortex, some hippocampal and olfactory bulb layers, prepiriform cortex, dorsal part of the caudate-putamen, globus pallidus, lateral septum, reticular thalamic nucleus, lateral habenular nucleus, circumventricular organs, nuclei of the medial hypothalamus, substantia nigra, interpeduncular nucleus, and mamillary body. These correspond to regions of the embryonic pial and ventricular brain surfaces, which undergo developmental alterations including growth and various forms of internalization. From this we conclude that in the adult brain, astrocytes of high GFAP-IR are derivatives of surface-contact glia, whereas those located in areas having developed by the local thickening of the neural tube wall show reduced or no GFAP-IR.

Mihály Kálmán

Papers

Nerve endings from rat brain tissue release copper upon depolarization. A possible role in regulating neuronal excitability.

Distribution of glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes in the rat brain. II. Mesencephalon, rhombencephalon and spinal cord.

Distribution of glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes in the rat brain. I. Forebrain.

Astroglial architecture of the carp (Cyprinus carpio) brain as revealed by immunohistochemical staining against glial fibrillary acidic protein (GFAP)

Mapping of glial fibrillary acidic protein‐immunoreactivity in the rat forebrain and mesencephalon by computerized image analysis