GLYCOCIRC · Sugars maketh the brain: investigating the role of neuronal glycocalyx in shaping the architecture of emerging circuits

Neuronal glycocalyx has been recently recognized as an active agent that contributes to neuronal synapse formation, neuron excitability as well as neuron-autonomous and microglia-dependent brain network remodelling. In particular, the glycan-terminating sialic acids, which often dominate the ends of the chains of glycoproteins and glycolipids on neuronal surface, are required for appropriate brain development and function. Interestingly, almost a fifth of sialic acid biology genes have human-specific changes and aberrant neuronal sialylation and desialylation are implicated in different neurodevelopmental and neuropsychiatric conditions. Thus, I hypothesize than neuronal glycocalyx and specifically its component sialic acid in particular have a critical role in the formation of unique human brain. Despite its recognized importance, there is still a lack of mechanistic understanding filling the knowledge gap how synapses are shaped by the dynamics of the glycocalyx. Therefore, here I propose to merge my expertise in biochemistry and neuroscience to tackle this challenging area of research to further our knowledge of brain sialome through evolutionary approach. We will use in vitro, ex vivo and in vivo models from humans, non-human primates and mouse that can be modified at genetic level for selective labelling and modification of neuronal cells and will combine it with advanced microscopy techniques as well as synaptic-level molecular analysis. We will demonstrate how the glycocalyx and sialic acid act as a defining factor for neural circuitry formation and refinement in developing brain, in particular through the interaction of neurons and their synapses with brain immune cells – microglia. Our results will advance our understanding of fundamental contribution of the glycocalyx to brain physiology and pathology with the translatability to human conditions, thus paving potential ways to develop treatment for brain network disorders.