Project description
Mechanisms of synaptic pruning in the developing brain
Neuron–microglial communication is mediated by both the formation of new synapses and the selective removal of unnecessary connections through synaptic pruning. Recent findings suggest that superfluous connections are eliminated by microglia, and 70 % of the connections in a primate cortex are lost within six months of life. Several eat-me signals in synaptic pruning have been identified, but spare-me signals limiting phagocytic elimination have not been established. Sialic acid in neuronal glycocalyx acts as a spare-me signal and prevents microglial phagocytosis through Siglec receptors, and aberrant regulation of sialic acid causes neuronal loss and embryonic lethality. The EU-funded SinGly project aims to investigate whether sialidases, glycocalyx recognising proteins, are developmentally regulated and study the role of sialic acid in synaptic pruning during neurodevelopment.
Objective
Effective neuron-microglial communication is a prerequisite to achieve the final connectome. It is mediated by both the formation of new synapses and selective removal of unnecessary connections through synaptic pruning. Recent evidences suggest that superfluous connections are eliminated by microglia. Almost 70% of the connections are lost in a primate cortex within six months of life. But what drives this selective elimination of so many synapses is a million-euro question. Identifying neuronal signals that differentiate weak synapses from the strong ones is an emerging frontier in cellular neuroscience. Several eat-me signals in synaptic pruning have been identified, but spare-me signals that limit phagocytic elimination of synapses are yet to be explored. Sialic acids on neuronal glycocalyx acts as spare-me signal and prevents microglial phagocytosis through Siglec receptors. Aberrant regulation of sialic acid caused neuronal loss and embryonic lethality. It is also becoming evident that sialic acid plays a key role in neurodevelopment, but the cellular and molecular mechanisms by which it regulates neurodevelopment is yet to be explored. This makes sialic acid an ideal candidate to evaluate its role in neurodevelopment. Hence, we aim to interrogate whether sialidases, glycocalyx recognizing proteins are developmentally regulated and also to define sialic acid’s role in synaptic pruning during neurodevelopment. We propose to implement gene, protein expression and metabolic profiling studies to investigate whether sialidases and glycocalyx recognizing proteins are developmentally regulated. Also, we will use fluorescent azido sugars in ex vivo cultures to visualise how sialic acid regulates synaptic pruning during neurodevelopment using superresolution STED microscopy. This paves a path to identify cellular and molecular mechanisms by which glycocalyx composition defines neuron-microglia interactions and thus circuit refinement through synaptic pruning.
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Programme(s)
Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
01513 Vilnius
Lithuania