Androgens show sex-dependent differences in myelination in immune and non-immune murine models of CNS demyelination

Abstract Neuroprotective, anti-inflammatory, and remyelinating properties of androgens are well-characterized in demyelinated male mice and men suffering from multiple sclerosis. However, androgen effects mediated by the androgen receptor (AR), have been only poorly studied in females who make low androgen levels. Here, we show a predominant microglial AR expression in demyelinated lesions from female mice and women with multiple sclerosis, but virtually undetectable AR expression in lesions from male animals and men with multiple sclerosis. In female mice, androgens and estrogens act in a synergistic way while androgens drive microglia response towards regeneration. Transcriptomic comparisons of demyelinated mouse spinal cords indicate that, regardless of the sex, androgens up-regulate genes related to neuronal function integrity and myelin production. Depending on the sex, androgens down-regulate genes related to the immune system in females and lipid catabolism in males. Thus, androgens are required for proper myelin regeneration in females and therapeutic approaches of demyelinating diseases need to consider male-female differences

Hedgehog: A Key Signaling in the Development of the Oligodendrocyte Lineage

The Hedgehog morphogen aroused an enormous interest since it was characterized as an essential signal for ventral patterning of the spinal cord two decades ago. The pathway is notably implicated in the initial appearance of the progenitors of oligodendrocytes (OPCs), the glial cells of the central nervous system which after maturation are responsible for axon myelination. In accordance with the requirement for Hedgehog signaling in ventral patterning, the earliest identifiable cells in the oligodendrocyte lineage are derived from the ventral ventricular zone of the developing spinal cord and brain. Here, we present the current knowledge about the involvement of Hedgehog signaling in the strict spatial and temporal regulation which characterizes the initiation and progression of the oligodendrocyte lineage. We notably describe the ability of the Hedgehog signaling to tightly orchestrate the appearance of specific combinations of genes in concert with other pathways. We document the molecular mechanisms controlling Hedgehog temporal activity during OPC specification. The contribution of the pathway to aspects of OPC development different from their specification is also highlighted especially in the optic nerve. Finally, we report the data demonstrating that Hedgehog signaling-dependency is not a universal situation for oligodendrocyte generation as evidenced in the dorsal spinal cord in contrast to the dorsal forebrain

Developmental and Repairing Production of Myelin: The Role of Hedgehog Signaling

Since the discovery of its role as a morphogen directing ventral patterning of the spinal cord, the secreted protein Sonic Hedgehog (Shh) has been implicated in a wide array of events contributing to the development, maintenance and repair of the central nervous system (CNS). One of these events is the generation of oligodendrocytes, the glial cells of the CNS responsible for axon myelination. In embryo, the first oligodendroglial cells arise from the ventral ventricular zone in the developing brain and spinal cord where Shh induces the basic helix-loop-helix transcription factors Olig1 and Olig2 both necessary and sufficient for oligodendrocyte production. Later on, Shh signaling participates in the production of oligodendroglial cells in the dorsal ventricular-subventricular zone in the postnatal forebrain. Finally, the modulation of Hedgehog signaling activity promotes the repair of demyelinated lesions. This mini-review article focuses on the Shh-dependent molecular mechanisms involved in the spatial and temporal control of oligodendrocyte lineage appearance. The apparent intricacy of the roles of two essential components of Shh signaling, Smoothened and Gli1, in the postnatal production of myelin and its regeneration following a demyelinating event is also highlighted. A deeper understanding of the implication of each of the components that regulate oligodendrogenesis and myelination should beneficially influence the therapeutic strategies in the field of myelin diseases

Cellules souches neurales et signalisation Notch

Les cellules souches neurales (CSN) sont essentielles au développement du système nerveux central et à sa réparation. Parmi les mécanismes contrôlant ces cellules, la signalisation Notch joue un rôle majeur. Chez l’embryon, elle permet le maintien des CSN pendant les différentes phases de développement du système nerveux central qui débute par la production des neurones, ou neurogenèse, et se poursuit par la gliogenèse conduisant aux astrocytes et oligodendrocytes. Au cours de la période post-natale et adulte, la signalisation Notch reste présente dans les principales aires de neurogenèse adulte, la zone sous-ventriculaire des ventricules latéraux et la zone sous-granulaire de l’hippocampe, où elle maintient la quiescence des CSN adultes, contribue au caractère hétérogène de ces cellules et exerce des effets pléiotropes au cours de la régénération du tissu neural lésé

Etude de la voie de signalisation Sonic Hedgehog dans le contrôle des progéniteurs oligodendrocytaires au cours de la démyélinisation

La voie de signalisation activée par la protéine Sonic Hedgehog (Shh) est connue pour son rôle majeur au cours de l embryogenèse et en particulier dans la prolifération et la spécification cellulaire ou encore le guidage axonal au cours de l établissement des structures du système nerveux. Depuis quelques années, ce morphogène a aussi été identifié comme un régulateur important de plusieurs processus physiologiques du cerveau adulte comme le maintien de la neurogenèse ou la régulation de l activité électrique de certains neurones (Traiffort et al., 2010). La suractivation de la voie Shh dans un cerveau sain entraine une augmentation significative de la prolifération des cellules progénitrices des oligodendrocytes (OPCs), la source des oligodendrocytes matures, les cellules responsables de la formation des gaines de myéline (Loulier et al., 2006). Au cours de ma thèse, j ai étudié le potentiel que représente l activation de la voie Shh dans la régulation de ces progéniteurs dans un contexte de démyélinisation. Pour cela, j ai utilisé une souris transgénique plp-GFP, chez laquelle la protéine fluorescente verte est exprimée par les cellules du lignage oligodendrocytaire. Après avoir caractérisé le profil d expression de la GFP dans le cerveau mature de ces souris, j ai mis au point un modèle de démyélinisation focale par injection stéréotaxique d un détergent spécifique de la myéline, la lysolécithine (LPC). J ai identifié les cellules du lignage oligodendrocytaire comme source directe de protéines Shh au sein de la lésion à un temps très précoce après l injection de LPC. Les gènes cibles de la voie Shh sont aussi fortement induits dans cette population cellulaire à une période plus tardive, correspondant à la différenciation des OPCs en cellules matures. L utilisation d adénovirus codant soit pour Shh lui-même soit pour son antagoniste physiologique Hip, m a permis de réaliser des expériences de gain et de perte de fonction et ainsi d analyser comment la modulation de la voie Shh peut influencer sur le processus de régénération des oligodendrocytes suite à une lésion. La surexpression de Shh permet d augmenter la prolifération des OPCs mais aussi d accélérer leur différenciation, aboutissant à un nombre plus élevé d oligodendrocytes matures plus précocement au cours du processus de remyélinisation. De plus, il est intéressant de constater que la densité des cellules astrocytaires et microgliales, notamment associées au processus inflammatoire, diminue dans la lésion chez les animaux ayant reçu l adénovirus Shh comparés au animaux contrôles. A l inverse, le blocage de la voie induit l arrêt complet de la production de nouveaux oligodendrocytes. Au-delà de l amélioration de notre compréhension de la physiologie et de la régulation du lignage oligodendrocytaire dans le cerveau adulte, l ensemble de ce travail montre de quelle manière la voie Shh peut représenter une nouvelle piste dans la recherche de cibles thérapeutiques dans les affections de la myéline telles que la sclérose en plaques.The Sonic Hedgehog (Shh) signaling pathway is known for its role during embryogenesis and in particular for controlling cell proliferation and specification, as well as axon guidance. In recent years, this morphogen has also been identified as an important regulator of several physiological processes in the adult brain such as the maintenance of neurogenesis or the regulation of the electrophysiological propreties of mature neurons (Traiffort et al., 2010). Overactivation of the Shh pathway in a healthy brain causes a significant increase in the proliferation of oligodendrocyte progenitor cells (OPCs), the source of mature oligodendrocytes, the cells responsible for the formation of myelin sheaths (Loulier et al., 2006).In my thesis, I studied the effects of the Shh pathway activation on OPC regulation in the context of demyelination. To that purpose, I used a plp-GFP transgenic mouse, in which the green fluorescent protein (GFP) is expressed by cells belonging to the oligodendrocyte lineage. After characterization of the expression pattern of GFP in the mature brain of these mice, I developed a model of focal demyelination by stereotaxic injection of lysolecithin (LPC). I identified the oligodendrocyte lineage cells as a source of Shh protein within the lesion, soon after the LPC injection. Target genes of the Shh pathway are also strongly induced in this cell population, at a time corresponding to the differentiation of OPCs into mature cells. The use of adenoviral vectors encoding either Shh itself or its physiological antagonist Hip allowed me to conduct gain- and loss-of-function experiments. This way I could analyze how the modulation of Shh pathway may influence the regeneration ofoligodendrocytes after injury. Shh overexpression increases the survival and proliferation of OPCs but also accelerates their differentiation, resulting in a higher number of mature oligodendrocytes earlier during the remyelination process. In addition, the density of astrocytes and microglia, associated with the inflammatory process, is decreased in animalsreceiving the Shh adenoviral vector compared to control animals. Altogether these effects are associated with a reduction of the lesion. Conversely, blocking the pathway induced a complete arrest of new oligodendrocyte production. Besides the fundamental knowledge gained about the molecular mechanism involved in the oligodendroglial precursor cells survival, proliferation, differentiation and myelin repair in vivo, this project should also give valuable insights concerning the potential use of pharmacological modulators of Shh signaling as a novel therapeutic approach for the treatment of multiple sclerosis and other myelin diseases.PARIS11-SCD-Bib. électronique (914719901) / SudocSudocFranceF

Inhibition of histamine versus acetylcholine metabolism as a mechanism of tacrine activity

International audienceFollowing tacrine administration i.p. to mice, the histamine N -methyltransferase activity of brain homogenates was more potently inhibited than the acetylcholinesterase activity (ID 50 of 5.3 mg/kg vs. 13.6 mg/kg). The formation of the metabolite, tele-methylhistamine, in brain of mice treated with an histamine H 3 receptor antagonist was abolished by tacrine with an ID 50 as low as 1.2 ± 0.4 mg/kg. The participation of histamine in the actions of tacrine and the relevance of histamine H 3 receptor antagonists in Alzheimer's disease are suggested

Interaction of mianserin, amitriptyline and haloperidol with guinea pig cerebral histamine H2 receptors studied with [125I]iodoaminopotentidine

International audienceTricyclic antidepressants were previously shown to potently inhibit the histamine-induced activation of H2 receptors linked to adenylate cyclase in cerebral membranes, and this effect was postulated to represent the mechanism of their therapeutic activity. However, these drugs were found to be much less potent (up to more than hundred-fold) at H2 receptors mediating cyclic AMP responses in intact cells. We have presently assessed whether this large difference in potency of antidepressants, also observed with haloperidol, results from a modified pharmacological specificity of the H2 receptor according to the medium composition. We have studied the binding of [125I]iodoaminopotentidine (125I-APT) to striatal or hippocampal membranes under various experimental conditions. At equilibrium the Kd of 125I-APT, a highly selective ligand for H2 receptors, was six times higher in a supplemented Tris buffer used for adenylate cyclase assays in cell-free systems than in a Krebs-Ringer medium used in studies with intact cells. The medium composition also variously affected the Ki values of the four compounds studied amitriptyline, mianserin, haloperidol and tiotidine. Whereas the Ki value of amitriptyline was little affected, that of the other compounds was four to five times lower in the supplemented Tris buffer than in the Krebs-Ringer medium. With the exception of tiotidine, the Ki values of other compounds in the binding test performed in this medium, were intermediate between those derived from the antagonism of histamine-induced cyclic AMP responses in membranes and intact cells. These data indicate that the difference between the two test responses is diversely attributable to several factors according to the compounds, the main ones being medium composition and possibly cell disruption

Astrocytes et microglies, des acteurs majeurs de la production de la myéline en conditions normales et pathologiques

International audienceMyelination is an essential process that consists of the ensheathment of axons by myelin. In the central nervous system (CNS), myelin is synthesized by oligodendrocytes. The proliferation, migration, and differentiation of oligodendrocyte precursor cells constitute a prerequisite before mature oligodendrocytes extend their processes around the axons and progressively generate a multilamellar lipidic sheath. Although myelination is predominately driven by oligodendrocytes, the other glial cells including astrocytes and microglia, also contribute to this process. The present review is an update of the most recent emerging mechanisms involving astrocyte and microglia in myelin production. The contribution of these cells will be first described during developmental myelination that occurs in the early postnatal period and is critical for the proper development of cognition and behavior. Then, we will report the novel findings regarding the beneficial or deleterious effects of astroglia and microglia, which respectively promote or impair the endogenous capacity of oligodendrocyte progenitor cells (OPCs) to induce spontaneous remyelination after myelin loss. Acute delineation of astrocyte and microglia activities and cross-talk should uncover the way towards novel therapeutic perspectives aimed at recovering proper myelination during development or at breaking down the barriers impeding the regeneration of the damaged myelin that occurs in CNS demyelinating diseases

Defective Oligodendroglial Lineage and Demyelination in Amyotrophic Lateral Sclerosis

International audienceMotor neurons and their axons reaching the skeletal muscle have long been considered as the best characterized targets of the degenerative process observed in amyotrophic lateral sclerosis (ALS). However, the involvement of glial cells was also more recently reported. Although oligodendrocytes have been underestimated for a longer time than other cells, they are presently considered as critically involved in axonal injury and also conversely constitute a target for the toxic effects of the degenerative neurons. In the present review, we highlight the recent advances regarding oligodendroglial cell involvement in the pathogenesis of ALS. First, we present the oligodendroglial cells, the process of myelination, and the tight relationship between axons and myelin. The histological abnormalities observed in ALS and animal models of the disease are described, including myelin defects and oligodendroglial accumulation of pathological protein aggregates. Then, we present data that establish the existence of dysfunctional and degenerating oligodendroglial cells, the chain of events resulting in oligodendrocyte degeneration, and the most recent molecular mechanisms supporting oligodendrocyte death and dysfunction. Finally, we review the arguments in support of the primary versus secondary involvement of oligodendrocytes in the disease and discuss the therapeutic perspectives related to oligodendrocyte implication in ALS pathogenesis