Experience-dependent regulation of dendrite morphogenesis and plasticity

National Institute Of Neurological Disorders And Stroke

Investigators

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Abstract

Over the recent years, our research group has utilized the Drosophila model to explore the concept of structural homeostatic plasticity during dendrite development. Through comprehensive genetic and imaging studies, we have unveiled specific molecular pathways that play essential roles in this intricate process. A significant aspect of our findings is the demonstration that fundamental principles governing dendrite plasticity are shared across various species, highlighting the central role of mechanisms that oversee the formation and maturation of synapses. In previous works, we published studies that elucidated two crucial molecular pathways responsible for orchestrating and supporting the development and maturation of cholinergic synapses. Specifically, these pathways involve neuron-glia lipid shuttling, facilitated by neuronal LpR receptors and glia-derived apolipoproteins, and the postsynaptic cholinergic singling, mediated by Drosophila nicotinic acetylcholine receptors (nAchR). Both pathways are targeted by activity-dependent transcriptional regulations and are indispensable for the development of dendrites and the proper functions of synapses. In the past two years, we have expanded on these findings and sought to identify new molecular targets within these two pathways. To achieve this, we have conducted multi-omics studies. We established brain lipid profiles using lipidomic and metabolomics analysis. We've also employed proximity labeling techniques to identify the molecular components of the protein complex centered around the postsynaptic nAchR subunits. Through these innovative experimental approaches, we have made breakthroughs in our research, including the identification of a previously unknown class of glia-derived lipid binding proteins. Furthermore, we've gained insights into the complex molecular organization of central cholinergic synapses at various stages of development in the Drosophila brain. These molecular identifications we made have been characterized through extensive genetic and imaging studies, confirming the validity of numerous candidate genes, many of which have mammalian homologs that remained unexplored. These findings open up new avenues for uncovering novel pathways critical for neurodevelopment, with direct implications for understanding human diseases.