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Prenatal alcohol exposure is a major non-genetic cause of structural and functional abnormalities of the central nervous system, the most severe form of which is fetal alcohol syndrome, and the effects of which persist throughout life, associating mental retardation, neurocognitive and behavioural disorders. Prenatal alcohol exposure is a public health issue, since currently most children are not early detected in the absence of the major signs consisting of characteristic cranio-facial dysmorphism and growth retardation. While numerous studies on neurodevelopmental abnormalities have been carried out in animals and the results of which are often contradictory, very little data is available in humans and mainly concerns children. In order to explain the symptoms of these children, we have conducted an ontogenetic study of interneurons and oligodendrocyte lineage, two essential events involved in the synchronization of neural networks. Using a cohort of 15 human fetuses at all stages of development and two postnatal cases aged three months and two years exposed to alcohol in utero, we studied the development of GABAergic and calretinergic interneurons as well as the characteristics of their vascular migration within the cortex. We identified an interneuronopathy consisting of a major generation delay in the production areas (ganglionic eminences) at the early stages of development and a mispositioning of calretinergic interneurons within the cortex of fetuses exposed to alcohol at later stages compared with age matched controls. This delay in generation also affects precursors of oligodendrocytes expressing PDGFRα, which then remain abnormally numerous at the expense of precursors and pre-oligodendrocytes expressing Olig2. The latter are virtually absent in the cortex of fetuses exposed to alcohol until the end of pregnancy. Interneuronopathy and the lack of oligodendroglial differentiation could partly explain the neurological disabilities observed in children and adults exposed in utero to alcohol, modulation of neuronal activity and myelination being essential for the establishment of neural networks and conduction of nerve outputs., L’exposition prénatale à l’alcool est une cause non génétique majeure d’anomalies structurales et fonctionnelles du système nerveux central dont la forme la plus sévère est le syndrome d’alcoolisation fœtale, et dont les effets perdurent tout au long de la vie, associant retard mental, troubles neurocognitifs et comportementaux. L’exposition prénatale à l’alcool est un enjeu de Santé Publique, car actuellement, la plupart des enfants ne sont pas précocement dépistés en l’absence des signes majeurs que sont la dysmorphie crânio-faciale caractéristique et le retard de croissance. Si de nombreuses études sur les anomalies neurodéveloppementales ont été réalisées chez l’animal et dont les résultats sont souvent contradictoires, très peu de données sont disponibles chez l’humain et concernent essentiellement l’enfant. Afin d’expliquer la symptomatologie de ces enfants, nous avons réalisé une étude de la mise en place des interneurones et de la glie de myélinisation, éléments essentiels intervenant dans la synchronisation des réseaux neuronaux. A partir d’une cohorte de 15 fœtus humains à tous les stades du développement et de deux cas post-nataux âgés de trois mois et deux ans exposés à l’alcool, nous avons étudié l’ontogenèse des interneurones GABAergiques et calrétininergiques ainsi que les caractéristiques de leur migration vasculaire dans le cortex. Nous avons identifié une interneuronopathie consistant en un retard majeur de génération dans les zones de production (éminences ganglionnaires) aux stades précoces de développement et une malposition des interneurones calrétininergiques au sein du cortex des fœtus alcoolisés aux stades plus tardifs comparativement à des contrôles appariés. Ce retard de génération touche également les précurseurs des oligodendrocytes exprimant le PDGFRα qui restent ensuite anormalement nombreux aux dépends des précurseurs et préoligodendrocytes exprimant Olig2. Ces derniers restent pratiquement absents dans le cortex des fœtus alcoolisés jusqu’en fin de la grossesse. L’interneuronopathie et le défaut de différentiation oligodendrogliale pourraient expliquer en partie les troubles neurologiques observés chez les enfants et adultes exposés in utero à l’alcool, la modulation de l’activité neuronale et la myélinisation étant indispensables à l’établissement des réseaux neuronaux et à la conduction des influx nerveux.

Magnetic Resonance Spectroscopy is based on the chemical shift property of the atom nuclei when a magnetic field is applied. This technique offers invaluable information about living tissues with special contribution to the diagnosis and prognosis of the central nervous system diseases. Concentration of several metabolites can be assessed in a reproducible manner by means of modern clinical scanners. N-acetyl-aspartate is regarded as a neuronal marker and its levels reflect the neuronal density with significant decreases in degenerative disease such as Alzheimer's disease. Choline-compounds reflect the cell's membrane turnover and degradation. Myo-inositol has emerged as a glial marker with increases in degenerative diseases. The major usefulness of MRS has been reported in brain tumors, degenerative disorders, myelination defects and encephalopathies. In this review we report the physical basis and the contribution of MR spectroscopy to the diagnosis and prognosis of several diseases of the Central Nervous System.

Diverse pathological changes occur in the white matter (WM) of patients with schizophrenia. Various microstructural alterations including a reduction in axonal number or diameter, reduced myelination, or poor coherence of fibers could account for these changes. Abnormal integrity of macromolecules such as myelin ('dysmyelination') can be studied by applying multiple modalities of WM imaging such as diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI) in parallel. Using ultra-high field (7 Tesla) MTI in 17 clinically stable patients with schizophrenia and 20 controls, we evaluated the voxelwise distribution of macromolecular WM abnormalities. Patients had a significant reduction in magnetization transfer ratio (MTR) in WM adjacent to visual processing regions and inferior temporal cortex (Cohen's d=1.54). Among the regions showing MTR reduction, a concurrent reduction in fractional anisotropy (FA) occurs proximal to the lingual gyrus. Multiple regression analysis revealed that the degree of FA reduction in the putatively 'dysmyelinated' regions in patients predicted impaired processing speed (PS; β=0.74; P=0.003), a core cognitive dysfunction in schizophrenia. In controls, MTR/FA in the occipito-temporal regions were not associated with PS. Our findings suggest that dysmyelination in visual processing regions is present in patients with schizophrenia with greatest cognitive and functional impairment. Combined DTI/MTI deficits in the occipito-temporal region may be an important variable when considering potential treatment targets for improving cognitive function in schizophrenia.

OMgp is selectively expressed in CNS by oligodendrocyte. However, its potential role(s) in oligodendrocyte development and myelination remain unclear. We show that OMgp null mice are hypomyelinated in their spinal cords, resulting in slower ascending and descending conduction velocities compared to wild-type mice. Consistent with the hypomyelination, in the MOG induced EAE model, OMgp null mice show a more severe EAE clinical disease and slower nerve conduction velocity compared to WT animals. The contribution of OMgp to oligodendrocyte differentiation and myelination was verified using cultured oligodendrocytes from null mice. Oligodendrocytes isolated from OMgp null mice show a significant decrease in the number of MBP+ cells and in myelination compared to wild-type mice. The dramatic effects of the OMgp KO in oligodendrocyte maturation in vivo and in vitro reveal a new and important function for OMgp in regulating CNS myelination.

Animal mutants with myelination defects, particularly those showing a similarity with human diseases, are useful models for the study of inherited neurological disorders.

Generating patient-specific oligodendrocyte progenitors capable of repairing myelination defects observed in multiple neurological afflictions holds great therapeutic potential. Recently in Nature Biotechnology, Najm et al. (2013) and Yang et al. (2013) generated these progenitors by direct reprogramming, bringing us closer to their use in disease analysis and autologous transplantation strategies.