Pre- and postsynaptic changes at the axo-glial synapses in white matter during de- and remyelination
Final Report Abstract
In Multiple Sclerosis (MS), mature oligodendrocytes are lost leaving axons at a high risk of degeneration. Remyelination prevents axons from degeneration, if oligodendrocyte precursor cells (OPCs) successfully differentiate into myelinating oligodendrocytes and re-establish lost internodes. The mechanisms of these interactions between OPCs and axons are currently under intense investigation. It is now generally assumed that electrical activity of axons regulates myelination, giving plasticity to the central nervous system. It is known from developmental myelination that neurons release neurotransmitter at contact-sites with OPCs, that OPCs express AMPA receptors to detect axonal signals and that these axon-glia synapses are lost as OPCs mature into oligodendrocytes exerting myelination. In addition, axons rearrange and re-express different sodium channel subunits in order to restore the ability to conduct action potentials under pathological conditions such as demyelination. This may in turn affect the release of neurotransmitter towards OPCs. In this project, changes at the axon-glia interface were analyzed during de- and remyelination. A model was set up where toxin-mediated demyelination was induced in transgenic mice expressing inducible GFP in OPCs and their progeny. Using this model, we found an increased number of GFP-expressing oligodendroglial cells in the caudal part of the corpus callosum compared to untreated controls. The length of GFP-positive protrusions was assessed, showing a decrease in length after toxin induced demyelination, indicating that newly generated protrusions of oligodendroglial cells during remyelination are shorter when compared to controls. Consistently, when analyzing the axons, we found an increase in the number of nodes of Ranvier in mice that had undergone de- and remyelination, indicating that newly formed internodes are shorter. Ultrastructural analysis of axons revealed an enhanced portion of unmyelinated axons showing vesicles in the cytoplasm after toxin-induced demyelination and during the recovery phase when compared to the controls. Enhanced staining of the corpus callosum for VGluT1, a marker for synaptic vesicles, was shown by immunohistochemistry. The precise location of VGluT1 positive vesicles along unmyelinated axons was shown immunogold labeling at the ultrastructural level. These findings indicate enhanced axonal signaling towards oligodendroglial cells after demyelination, presumably to increase the amount of remyelination. In addition, a functional readout was applied, revealing changes in the properties of compound action potentials in different fiber bundles of the corpus callosum during demyelination as well as during the recovery period of remyelination. The results highlight the flexibility of axons towards changes in the glial compartment and depict the structural changes they undergo upon myelin removal. Understanding how neuronal activity controls the behavior of oligodendroglial cells is essential to find new targets to develop new therapies that aim at enhancing remyelination and axon preservation in neurodegenerative diseases.
Publications
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(2016) N- and L-type voltage-gated calcium channels mediate fast calcium transients in axonal shafts of mouse peripheral nerve. Front. Cellular Neurosci. June, Volume 10, Article 135
Barzan R, Pfeiffer F, Kukley M
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Setting up a model to investigate sodium channel distribution during remyelination. Gordon Research Conference ‘Myelin’, Italy, 05/2016
Friederike Pfeiffer, Maria Kukley
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Axonal changes during myelin remodeling. 11th FENS Forum of Neuroscience, Berlin, Germany, 07/2018
Friederike Pfeiffer, Petra Fallier-Becker
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(2019) Structural adaption of axons during de- and remyelination in the Cuprizone mouse model. Brain Pathology 29, 675-692
Pfeiffer F, Frommer-Kaestle G, Fallier-Becker P
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Axonal changes upon toxin-induced myelin remodeling. 13th Göttingen Meeting of the German Neuroscience Society, Göttingen, Germany, 03/2019
Friederike Pfeiffer, Petra Fallier-Becker
