Neuronal activity-dependent myelin repair after stroke.

Brain tissue undergoes substantial activity-dependent reorganisation after stroke due to neuronal plasticity, leading to partial functional recovery in patients. Concurrent myelin repair is crucial for proper neuronal network function and reorganisation. Myelin repair after stroke might occur as myelin plasticity or as remyelination through the recruitment and differentiation of oligodendrocyte precursor cells (OPCs), which become myelin-forming oligodendrocytes (OLs). These two processes might share a similar guiding mechanism, which is postulated to depend on neuronal activity and glutamate signaling to OPCs. However, with ageing, the ability of OPCs to differentiate into myelinating OLs decreases due to changes in their ion channel and neurotransmitter receptor expression profile, rendering them less sensitive to neuronal activity. Because of their unique ability to replace damaged OLs, OPCs represent a potential therapeutic target for myelin repair in the context of stroke

A Matter of State: Diversity in Oligodendrocyte Lineage Cells.

Oligodendrocyte precursor cells (OPCs) give rise to oligodendrocytes which myelinate axons in the central nervous system. Although classically thought to be a homogeneous population, OPCs are reported to have different developmental origins and display regional and temporal diversity in their transcriptome, response to growth factors, and physiological properties. Similarly, evidence is accumulating that myelinating oligodendrocytes display transcriptional heterogeneity. Analyzing this reported heterogeneity suggests that OPCs, and perhaps also myelinating oligodendrocytes, may exist in different functional cell states. Here, we review the evidence indicating that OPCs and oligodendrocytes are diverse, and we discuss the implications of functional OPC states for myelination in the adult brain and for myelin repair

Neuronal activity regulates remyelination via glutamate signalling to oligodendrocyte progenitors.

Myelin regeneration can occur spontaneously in demyelinating diseases such as multiple sclerosis (MS). However, the underlying mechanisms and causes of its frequent failure remain incompletely understood. Here we show, using an in-vivo remyelination model, that demyelinated axons are electrically active and generate de novo synapses with recruited oligodendrocyte progenitor cells (OPCs), which, early after lesion induction, sense neuronal activity by expressing AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)/kainate receptors. Blocking neuronal activity, axonal vesicular release or AMPA receptors in demyelinated lesions results in reduced remyelination. In the absence of neuronal activity there is a ∼6-fold increase in OPC number within the lesions and a reduced proportion of differentiated oligodendrocytes. These findings reveal that neuronal activity and release of glutamate instruct OPCs to differentiate into new myelinating oligodendrocytes that recover lost function. Co-localization of OPCs with the presynaptic protein VGluT2 in MS lesions implies that this mechanism may provide novel targets to therapeutically enhance remyelination.This work was supported by the Medical Research Council (R.T.K, R.J.M.F and H.O.B.G. G0701476; K.V. and R.T.K 1233560), Wellcome Trust (R.T.K. and K.A.E. 091543/Z/10/Z), Marie Curie training programme Axregen EC FP7 ITN (I.L. and R.T.K 214003), and core support grant from the Wellcome Trust and MRC to the Wellcome Trust – Medical Research Council Cambridge Stem Cell Institute.This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ncomms951

Aberrant methylation of tRNAs links cellular stress to neuro-developmental disorders.

Mutations in the cytosine-5 RNA methyltransferase NSun2 cause microcephaly and other neurological abnormalities in mice and human. How post-transcriptional methylation contributes to the human disease is currently unknown. By comparing gene expression data with global cytosine-5 RNA methylomes in patient fibroblasts and NSun2-deficient mice, we find that loss of cytosine-5 RNA methylation increases the angiogenin-mediated endonucleolytic cleavage of transfer RNAs (tRNA) leading to an accumulation of 5' tRNA-derived small RNA fragments. Accumulation of 5' tRNA fragments in the absence of NSun2 reduces protein translation rates and activates stress pathways leading to reduced cell size and increased apoptosis of cortical, hippocampal and striatal neurons. Mechanistically, we demonstrate that angiogenin binds with higher affinity to tRNAs lacking site-specific NSun2-mediated methylation and that the presence of 5' tRNA fragments is sufficient and required to trigger cellular stress responses. Furthermore, the enhanced sensitivity of NSun2-deficient brains to oxidative stress can be rescued through inhibition of angiogenin during embryogenesis. In conclusion, failure in NSun2-mediated tRNA methylation contributes to human diseases via stress-induced RNA cleavage

Neuregulin and BDNF Induce a Switch to NMDA Receptor-Dependent Myelination by Oligodendrocytes

<div><p>Myelination is essential for rapid impulse conduction in the CNS, but what determines whether an individual axon becomes myelinated remains unknown. Here we show, using a myelinating coculture system, that there are two distinct modes of myelination, one that is independent of neuronal activity and glutamate release and another that depends on neuronal action potentials releasing glutamate to activate NMDA receptors on oligodendrocyte lineage cells. Neuregulin switches oligodendrocytes from the activity-independent to the activity-dependent mode of myelination by increasing NMDA receptor currents in oligodendrocyte lineage cells 6-fold. With neuregulin present myelination is accelerated and increased, and NMDA receptor block reduces myelination to far below its level without neuregulin. Thus, a neuregulin-controlled switch enhances the myelination of active axons. <i>In vivo</i>, we demonstrate that remyelination after white matter damage is NMDA receptor-dependent. These data resolve controversies over the signalling regulating myelination and suggest novel roles for neuregulin in schizophrenia and in remyelination after white matter damage.</p></div

Surpassing light-induced cell damage in vitro with novel cell culture media

AbstractLight is extensively used to study cells in real time (live cell imaging), separate cells using fluorescence activated cell sorting (FACS) and control cellular functions with light sensitive proteins (Optogenetics). However, photo-sensitive molecules inside cells and in standard cell culture media generate toxic by-products that interfere with cellular functions and cell viability when exposed to light. Here we show that primary cells from the rat central nervous system respond differently to photo-toxicity, in that astrocytes and microglia undergo morphological changes, while in developing neurons and oligodendrocyte progenitor cells (OPCs) it induces cellular death. To prevent photo-toxicity and to allow for long-term photo-stimulation without causing cellular damage, we formulated new photo-inert media called MEMO and NEUMO, and an antioxidant rich and serum free supplement called SOS. These new media reduced the detrimental effects caused by light and allowed cells to endure up to twenty times more light exposure without adverse effects, thus bypassing the optical constraints previously limiting experiments.</jats:p

Spiking and nonspiking classes of oligodendrocyte precursor glia in CNS white matter

A defining feature of glial cells has been their inability to generate action potentials. We show here that there are two distinct types of morphologically identical oligodendrocyte precursor glial cells (OPCs) in situ in rat CNS white matter. One type expresses voltage-gated sodium and potassium channels, generates action potentials when depolarized and senses its environment by receiving excitatory and inhibitory synaptic input from axons. The other type lacks action potentials and synaptic input. We found that when OPCs suffered glutamate-mediated damage, as occurs in cerebral palsy, stroke and spinal cord injury, the action potential-generating OPCs were preferentially damaged, as they expressed more glutamate receptors, and received increased spontaneous glutamatergic synaptic input in ischemia. These data challenge the idea that only neurons generate action potentials in the CNS and imply that the development of therapies for demyelinating disorders will require defining which OPC type can carry out remyelination. © 2008 Nature Publishing Group

Effect of NRG and NMDA receptor block on myelination.

<p>(A, B) High-magnification views of a myelinating oligodendrocyte (A) with MBP (green) expressed in processes wrapping around axons expressing NF 160/200 (NF, red), and of a nonmyelinating oligodendrocyte (B) with MBP expressed (in a more patchy and often diffuse manner) in processes that are not aligned with axons. Myelination was quantified as the fraction of all MBP-expressing oligodendrocytes that provided a thick straight myelin sheath to at least one axon. (C–F) Myelinating processes (MBP, green) wrapping DRG axons (NF, red) in control conditions (C), in the presence of MK-801 (D), in the presence of NRG (E), and in the presence of NRG and MK-801 (F). Filled and open arrows show some myelinating and nonmyelinating oligodendrocytes. Graphs show fraction of oligodendrocytes that are myelinating, versus fraction of area occupied by DRG processes, for 30 images of each coverslip from which the specimen images shown were taken, best fit with a linear dependence of myelination on axon density.</p