Glutamate transporters as regulators of CNS myelination

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 DESCRIPTION (provided by applicant): Oligodendrocytes (OLGs), the myelinating cells of the central nervous system (CNS), undergo extensive changes in morphology when they mature first from bipolar OLG progenitors into premyelinating OLGs extending a complex and expanded process network and then into mature OLGs generating the myelin sheath. The morphological changes associated with this lineage progression are to a large extent driven by changes in the organization of the actin cytoskeleton, which require a well-coordinated dynamic turnover of actin filaments and are thought to be regulated by extracellular signals, which may, at least in part, be axon-derived. Despite intensive research, however, the signaling pathways involved in regulating such extracellular signal-regulated changes in actin cytoskeleton-driven OLG morphology, i.e. OLG morphogenesis, and CNS myelination are currently only poorly characterized. Notably, both changes in the extracellular milieu and a misregulation of actin cytoskeletal mechanisms have been proposed to contribute to the limitations in OLG morphogenesis and remyelination as seen within the CNS of the major demyelinating disease in human, Multiple Sclerosis (MS). Thus and in an attempt to identify novel therapeutic targets for the treatment of MS, our long-term goal is to identify and characterize signaling axes that promote developmental OLG morphogenesis and CNS myelination via an extracellular signal to actin cytoskeleton pathway but are misregulated within MS lesions. In this regard, our preliminary data suggest that a signaling axis involving the activity of sodium- dependent glutamate transporters and subsequent changes in the actin-binding activity of calcium/calmodulin- dependent protein kinase IIß (CaMKIIß) is critical for efficient OLG morphogenesis and the generation of a myelin sheath of proper thickness (g-ratio). Notably, our preliminary data together with previously published findings point toward a misregulation of this signaling axis within MS lesions. Based on our preliminary data, we thus formulate the central hypothesis that efficient myelination, i.e. the establishment of myelin with a proper g-ratio, is regulated by a glutamate transporter-CaMKIIß-actin cytoskeleton axis that is operative within differentiating OLGs. To address the above stated central hypothesis we propose the completion of the following two specific aims: 1) to characterize in vivo the role of the apparentl functionally predominant sodium-dependent glutamate transporter in differentiating OLGs, GLT-1, in regulating developmental myelination and 2) to characterize in vitro the role of the glutamate transporter-CaMKIIß-actin cytoskeleton axis in regulating OLG morphogenesis. We anticipate that these experiments will build the basis for continuing studies in which to define strategies to specifically target CaMKIIß's unique actin binding properties and/or GLT-1 signaling as an attempt toward the development of novel remyelination promoting therapeutic strategies and toward improving the treatment of neurologic diseases associated with CNS demyelination.