Localized calcium accumulations prime synapses for phagocyte removal in cortical neuroinflammation

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 5 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 10 inflammatory gray matter lesions that is amenable to immunomodulatory therapy. HIGHLIGHTS:• Widespread, but transient loss of synapses in inflammatory lesions and beyond • Reversible impairment of neuronal firing and circuit function in the inflamed cortex • Calcium dyshomeostasis of single spines precedes swift synapse loss 20• Phagocyte-mediated spine pruning as targetable mechanism of synapse loss Jafari, Schumacher, Snaidero et al.2

Sex differences in the neuronal transcriptome and synaptic mitochondrial function in the cerebral cortex of a multiple sclerosis model

“…Cerebral cortex atrophy in MS correlates with worsening disability, as measured by the Expanded Disability Status Scale (EDSS) (9)(10)(11). Cortical pathology in MS includes neuronal damage and synaptic loss (12)(13)(14)(15)(16)(17). A better understanding of neurodegeneration in the cerebral cortex at the molecular level is needed.…”