Localized calcium accumulations prime synapses for phagocyte removal in cortical neuroinflammation

Jafari, M.; Schumacher, A.-M.; Snaidero, N.; Neziraj, T.; Ullrich Gavilanes, E. M.; Jürgens, T.; Florez Weidinger, J. D.; Schmidt, S. S.; Beltran, E.; Hagan, N.; Woodworth, L.; Ofengeim, D.; Gans, J.; Wolf, F.; Kreutzfeldt, M.; Portugues, R.; Merkler, D.; Misgeld, T.; Kerschensteiner, M.

doi:10.1101/758193

bioRxiv · 10.1101/758193

Localized calcium accumulations prime synapses for phagocyte removal in cortical neuroinflammation

Jafari, M.·Schumacher, A.-M.·Snaidero, N.·Neziraj, T.·Ullrich Gavilanes, E. M.·Jürgens, T.·Florez Weidinger, J. D.·Schmidt, S. S.·Beltran, E.·Hagan, N.·Woodworth, L.·Ofengeim, D.·Gans, J.·Wolf, F.·Kreutzfeldt, M.·Portugues, R.·Merkler, D.·Misgeld, T.·Kerschensteiner, M.

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Abstract

Cortical pathology contributes to chronic cognitive impairment of patients suffering from the neuroinflammatory disease multiple sclerosis (MS). How such gray matter inflammation affects neuronal structure and function is not well understood. Here we use functional and structural in vivo imaging in a mouse model of cortical MS to demonstrate that bouts of cortical inflammation disrupt cortical circuit activity coincident with a widespread but transient loss of dendritic spines. Spines destined for removal show a local calcium accumulation and are subsequently removed by invading macrophages and activated microglia. Targeting phagocyte activation with a new antagonist of the colony-stimulating factor 1 receptor prevents cortical synapse loss. Overall, our study identifies synapse loss as a key pathological feature of inflammatory gray matter lesions that is amenable to immunomodulatory therapy.\n\nHIGHLIGHTSO_LIWidespread, but transient loss of synapses in inflammatory lesions and beyond\nC_LIO_LIReversible impairment of neuronal firing and circuit function in the inflamed cortex\nC_LIO_LICalcium dyshomeostasis of single spines precedes swift synapse loss\nC_LIO_LIPhagocyte-mediated spine pruning as targetable mechanism of synapse loss\nC_LI

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Jafari, M., Schumacher, A.-M., Snaidero, N., Neziraj, T., Ullrich Gavilanes, E. M., Jürgens, T., Florez Weidinger, J. D., Schmidt, S. S., Beltran, E., Hagan, N., Woodworth, L., Ofengeim, D., Gans, J., Wolf, F., Kreutzfeldt, M., Portugues, R., Merkler, D., Misgeld, T., Kerschensteiner, M.. 2019-09-04. Localized calcium accumulations prime synapses for phagocyte removal in cortical neuroinflammation. https://doi.org/10.1101/758193

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