Experience-dependent regulation of dendrite morphogenesis and plasticity

National Institute Of Neurological Disorders And Stroke

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Abstract

Neuronal plasticity accompanying development and experience-dependent processes facilitates the establishment and refinement of the nervous system, while presenting significant challenges to the functional stability of neural networks. To cope with these perturbations, the nervous system uses a variety of compensatory mechanisms. Recent studies indicate that structural plasticity serves as a major component of neuronal homeostasis. However, the cellular and molecular mechanisms underlying structural homeostasis remain largely unexplored. To investigate molecular pathways regulating activity-dependent dendrite plasticity, we employed ventral lateral neurons (LNvs) in the Drosophila larval visual circuit as a model system. During the past few years, we performed forward genetic screens and cell-type specific RNA-seq analyses. These combined approaches helped us identify a large number of novel candidate genes regulating dendrite development, maturation and plasticity. In addition, using high resolution cellular and functional imaging, we established new methods to quantitatively assess dendrite expansion and dynamics, synapse formation and activity-evoked physiological responses. These efforts lead us to uncovered specific cellular and molecular pathways regulating structural homeostasis associated with LNv dendrite development. Specifically, neuronal lipid transport, supported by LpR receptors and glia-derived apolipoproteins, as well as the postsynaptic cholinergic signaling, mediated by Drosophila nAchR receptors, are both targeted by activity-dependent transcriptional regulations and are critical for supporting LNv dendrite development and synaptic functions. Importantly, our findings demonstrate that the fundamental principles guiding neural plasticity are shared across species, and the mechanisms controlling synapse formation and maturation appear to be their core elements. Taken together, our studies identified novel molecular targets and cellular processes involved in regulating activity-dependent structural and functional plasticity, contributing to a better understanding of the etiology of human neurodevelopmental disorders.