Descrizione del progetto
Meccanismi di potatura sinaptica nel cervello in via di sviluppo
La comunicazione neurone-microglia è mediata sia dalla formazione di nuove sinapsi sia dalla rimozione selettiva di collegamenti non necessari attraverso la potatura sinaptica. Recenti scoperte suggeriscono che i collegamenti superflui vengono eliminati dalla microglia e che il 70 % dei collegamenti in una corteccia di un primate vengono persi entro sei mesi di vita. Sono stati identificati diversi segnali «eat-me» (mangiami) nella potatura sinaptica, ma non sono stati stabiliti segnali «spare-me» (risparmiami) che limitano l’eliminazione fagocitica. L’acido sialico presente nel glicocalice neuronale funge da segnale «spare-me» e previene la fagocitosi microgliale attraverso i recettori Siglec, mentre la regolazione aberrante dell’acido sialico provoca perdita neuronale e letalità embrionale. Il progetto SinGly, finanziato dall’UE, mira a studiare se le sialidasi, le proteine che riconoscono il glicocalice, siano regolate a livello di sviluppo e studia il ruolo dell’acido sialico nella potatura sinaptica durante il neurosviluppo.
Obiettivo
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.
Campo scientifico
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Meccanismo di finanziamento
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinatore
01513 Vilnius
Lituania