Vesicular glutamate release from central axons contributes to myelin damage

Doyle, Sean; Hansen, Daniel Bloch; Vella, Janis; Bond, Peter; Harper, Glenn; Zammit, Christian; Valentino, Mario; Fern, Robert

doi:10.1038/s41467-018-03427-1

Cited by 61 publications

(59 citation statements)

References 46 publications

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“…It is well established that vesicular Glu release from the axons in WM contributes to action‐potential propagation . It has been also documented that chronically increased glutamatergic release from central nervous system (CNS) axons may lead to myelin damage . Increased Glu detectable by MRS in earlier disease stages may thus precede the macroscopic WM lesions often observed in MPAN patients with long‐standing disease .…”

Section: Discussionmentioning

confidence: 68%

“…31 It has been also documented that chronically increased glutamatergic release from central nervous system (CNS) axons may lead to myelin damage. 32 Increased Glu detectable by MRS in earlier disease stages may thus precede the macroscopic WM lesions often observed in MPAN patients with long-standing disease. 7 Atrophy of the thalamus and striatum detected by the volumetric analysis further confirms that MPAN affects not only GP and SN, but also causes global CNS abnormalities.…”

Section: Mpan Findingsmentioning

confidence: 97%

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Brain Iron and Metabolic Abnormalities in C19orf12 Mutation Carriers: A 7.0 Tesla MRI Study in Mitochondrial Membrane Protein–Associated Neurodegeneration

et al. 2019

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Background Mitochondrial membrane protein‐associated neurodegeneration is an autosomal‐recessive disorder caused by C19orf12 mutations and characterized by iron deposits in the basal ganglia. Objectives The aim of this study was to quantify iron concentrations in deep gray matter structures using quantitative susceptibility mapping MRI and to characterize metabolic abnormalities in the pyramidal pathway using 1H MR spectroscopy in clinically manifesting membrane protein‐associated neurodegeneration patients and asymptomatic C19orf12 gene mutation heterozygous carriers. Methods We present data of 4 clinically affected membrane protein‐associated neurodegeneration patients (mean age: 21.0 ± 2.9 years) and 9 heterozygous gene mutation carriers (mean age: 50.4 ± 9.8 years), compared to age‐matched healthy controls. MRI assessments were performed on a 7.0 Tesla whole‐body system, consisting of whole‐brain gradient‐echo scans and short echo time, single‐volume MR spectroscopy in the white matter of the precentral/postcentral gyrus. Quantitative susceptibility mapping, a surrogate marker for iron concentration, was performed using a state‐of‐the‐art multiscale dipole inversion approach with focus on the globus pallidus, thalamus, putamen, caudate nucleus, and SN. Results and Conclusion In membrane protein‐associated neurodegeneration patients, magnetic susceptibilities were 2 to 3 times higher in the globus pallidus (P = 0.02) and SN (P = 0.02) compared to controls. In addition, significantly higher magnetic susceptibility was observed in the caudate nucleus (P = 0.02). Non‐manifesting heterozygous mutation carriers exhibited significantly increased magnetic susceptibility (relative to controls) in the putamen (P = 0.003) and caudate nucleus (P = 0.001), which may be an endophenotypic marker of genetic heterozygosity. MR spectroscopy revealed significantly increased levels of glutamate, taurine, and the combined concentration of glutamate and glutamine in membrane protein‐associated neurodegeneration, which may be a correlate of corticospinal pathway dysfunction frequently observed in membrane protein‐associated neurodegeneration patients. © 2019 International Parkinson and Movement Disorder Society

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Section: Discussionmentioning

confidence: 68%

Section: Mpan Findingsmentioning

confidence: 97%

Brain Iron and Metabolic Abnormalities in C19orf12 Mutation Carriers: A 7.0 Tesla MRI Study in Mitochondrial Membrane Protein–Associated Neurodegeneration

et al. 2019

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“…NMDARs are distributed in both myelin and posterior synaptic membranes. These receptors not only trigger and induce long-term enhancement (LTP) in the hippocampus but also prevent myelin necrosis after white matter damage (Bliss, Collingridge, & Morris, 2014;Doyle et al, 2018;Lundgaard et al, 2013;Paoletti, Bellone, & Zhou, 2013). NMDARs are both ligand and voltage-gated ion channels.…”

Section: Discussionmentioning

confidence: 99%

Potential synaptic plasticity‐based Shenzhiling oral liquid for a SAD Mouse Model

Wang

Chen

et al. 2019

Brain and Behavior

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Background Synaptic plasticity is the basis of memory formation. The pathological manifestations of abnormal glucose metabolism in the nervous system of sporadic Alzheimer's disease (SAD) may affect synaptic plasticity, thus causing memory damage. As a traditional Chinese medicine compound preparation, the mechanism by which Shenzhiling (SZL) oral liquid can alleviate the cognitive impairment of SAD by improving synaptic plasticity remains unclear. Objective: This article mainly discusses whether SZL can exert a protective synaptic effect as mediated by glutamate receptors and glycogen synthesis kinase 3β (GSK3β); further, it discusses whether SZL can improve cognitive function in SAD. Methods C57BL/6 mice were used as a SAD model after injection with streptozotocin (STZ) into the bilateral lateral ventricles; mice of the same background were injected with artificial cerebrospinal fluid into bilateral ventricles and were used as a control group. After 3 months of exposure to the intervention, the step‐down test was carried out. Western blot was used to detect the levels of NMDAR2B, p‐NMDAR2B, mGlu5, GSK3β, and p‐GSK3β in the hippocampus of mice. Immunohistochemical analysis was used to observe the number of GSK3β‐positive cells in the CA1 region of mouse hippocampus. Results The memory retention ability of mice was significantly improved after 3 months of SZL treatment, and the expression levels of NMDAR2B, mGlu5, and GSK3β were significantly changed. Conclusion Shenzhiling provides a potential for the treatment for SAD with traditional Chinese medicine.

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“…In contrast, by using a non-EM approach, we have detected PSD-95 in sheaths. What explains 42 . This is consistent with the observation that vesicular release from certain axons profoundly modulates their myelin profiles, while vesicular release is dispensable for the myelination of other classes of axons 43 .…”

Section: Discussionmentioning

confidence: 99%

Synaptic proteins expressed by oligodendrocytes mediate CNS myelination

Hughes

Appel

2018

Preprint

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Oligodendrocytes ensheath neuronal axons with myelin, a proteolipid-rich membrane that increases conduction velocity and provides trophic support. Our lab and others have provided evidence that vesicular release from neurons promotes myelin sheath growth. Complementarily, transcriptomic and proteomic approaches have revealed that oligodendrocytes express many proteins that allow dendrites to sense and respond to vesicular release at synapses. Do axon-myelin contacts use similar communication mechanisms as nascent synapses to form myelin sheaths on axons? To test this, we used fusion proteins to track synaptic vesicle localization and membrane fusion within spinal cord axons of zebrafish larvae during developmental myelination. Additionally, we used a CRISPR/Cas9-mediated GAL4 enhancer trap and genetically-encoded intrabody to detect expression and localization of PSD-95, a component of dendritic postsynaptic complexes, within oligodendrocytes. We found that synaptic vesicles accumulate at ensheathment sites over time and are exocytosed with variable patterning underneath myelin sheaths. Accordingly, we also found that most, but not all sheaths localized PSD-95 with patterning similar to exocytosis site location within the axon. By querying published transcriptome databases, we found that oligodendrocytes express numerous transsynaptic adhesion molecules that function across synapses to promote synapse formation and maturation. Disruption of candidate PDZ-binding transsynaptic adhesion proteins in oligodendrocytes revealed that these proteins have variable effects on sheath length and number. We focused on one candidate, Cadm1b (SynCAM1), and demonstrated that it localized to myelin sheaths where both its PDZ binding and extracellular adhesion to axons are required for myelin sheath growth. Our work reveals shared mechanisms of synaptic and myelin plasticity and provides new targets for mechanistic unraveling of activity-regulated myelination.Communication in the central nervous system (CNS) depends on billions of connections. Synapses, the connections between neurons, are plastic structures that grow and change with experience-evoked neuronal activity. Additionally, connections form between neurons and oligodendrocytes, the myelinating cell type of the CNS. Myelin sheaths also are plastic structures, mutable in length, number, and thickness 1-3 . Some of this plasticity may be triggered by experience, because motor learning paradigms increase myelination 4,5 and social and sensory deprivation paradigms reduce myelination of relevant brain regions 2,6,7 . What accounts for myelin sheath plasticity? One possibility is that neuronal activity tunes ensheathment, similar to activitydependent plasticity at synapses 8 . Consistent with this possibility, Demerens and colleagues first demonstrated more than 20 years ago that inhibiting action potential propagation with tetrodotoxin (TTX) reduced myelination of cultured neurons 9 . Activity-mediated communication from axons to myelin sheaths could ensure that active neuron...

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Vesicular glutamate release from central axons contributes to myelin damage

Cited by 61 publications

References 46 publications

Brain Iron and Metabolic Abnormalities in C19orf12 Mutation Carriers: A 7.0 Tesla MRI Study in Mitochondrial Membrane Protein–Associated Neurodegeneration

Brain Iron and Metabolic Abnormalities in C19orf12 Mutation Carriers: A 7.0 Tesla MRI Study in Mitochondrial Membrane Protein–Associated Neurodegeneration

Potential synaptic plasticity‐based Shenzhiling oral liquid for a SAD Mouse Model

Synaptic proteins expressed by oligodendrocytes mediate CNS myelination

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