Complement Receptor 3 – The Microglial Engulfment Receptor that Facilitates Synaptic Elimination in a Multiple Sclerosis-Relevant Mouse-Model of Demyelinating Disease? – UROP Symposium

Complement Receptor 3 – The Microglial Engulfment Receptor that Facilitates Synaptic Elimination in a Multiple Sclerosis-Relevant Mouse-Model of Demyelinating Disease?

Sarh Hossein Altaweel

Research Mentor(s): Sebastian Werneburg
Program: CCSFP
Authors: Sarh Altaweel, Jackson McGrath, Chun-Wei Chen, PhD, Dorothy P. Schafer, PhD, Sebastian Werneburg, PhD

Abstract

Multiple sclerosis (MS) is a demyelinating neurodegenerative disease that leads to the degeneration of central nervous system (CNS) circuits and neurological dysfunction. While known hallmark pathologies include demyelination, neuroinflammation, and neuroaxonal loss, only little is known about what happens to synapses and neuronal connectivity in MS. While a few previous studies have found synapse loss in MS, the mechanisms underlying the disruption of synaptic networks remained unknown. Previous work in the Werneburg lab using the visual system, which is commonly affected in MS patients, has shown engulfment and removal of synapses by microglia in postmortem MS tissue and in multiple MS-relevant models. This microglial synapse elimination was dependent on the innate immune signaling molecule complement factor C3, which accumulated at retinogeniculate synapses and allowed for the recognition and removal by microglia. However, the microglial receptor interacting with C3 remained elusive. Previous work has identified complement receptor 3 (CR3) as the microglial engulfment receptor for synaptic pruning in the healthy developing brain, however, the same receptor has not yet been tested for synapse removal in demyelinating disease. Here, we test the potential role of CR3 in synapse engulfment in demyelinating disease by a comparative assessment of synaptic densities and local inflammation after EAE induction in CR3 knockout mice and wildtype littermates. The results of these experiments will give us important new insights into microglia-mediated synaptic elimination, which interferes with circuit function and may lead to the identification of new therapeutic targets for MS intervention.

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