| dc.description.abstract | Multicellular organisms adapt to the environment by sensing it and reacting to it through neuronal networks that are in place to transform a stimulus into a behavioral effect. A functional nervous system requires pruning and refinement of established synapses during development. However, the cellular pathways that govern these key remodeling events remain elusive. The present work addresses this gap in knowledge by identifying a pathway that remodels the synaptic terminals of neurons in the nematode Caenorhabditis elegans.
In this paradigm, Dorsal D (DD) motor neurons initially synapse with ventral muscles but then switch their inputs to dorsal muscles. Using this developmental event of synaptic remodeling in a genetically tractable and transparent organism, we have uncovered new aspects of synapse elimination and how it can be coupled to the assembly of new boutons.
The Miller Lab has previously shown that neural activity, regulated by the DEG/ENaC cation channel, UNC-8, and calcineurin/TAX-6, drive disassembly of ventral GABAergic presynaptic terminals. Our new in vivo findings confirm that ENaC/UNC-8 promotes Ca++ transients during evoked transmission. Additional genetics and live-imaging experiments point to a downstream cellular mechanism in which presynaptic components are removed by a pathway resembling Activity-Dependent Bulk Endocytosis (ADBE). Our findings suggest that a native mechanism (ADBE) that normally functions to maintain neurotransmitter release at local synapses has been effectively repurposed, in this case, to dismantle presynaptic terminals.
Additional findings have provided a novel explanation for this unanticipated phenomenon. As we have determined that endogenous material from dismantled synapses is recycled for assembly at new dorsal boutons. This coupling of synapse elimination and formation is controlled by parallel pathways that differentially regulate the elimination of synaptic vesicle proteins and components of the active zone. Our observations suggest that synaptic disassembly is likely orchestrated by distinct cellular routes that ensure the specificity and fidelity of synaptic destruction and reassembly.
Finally, we present the systematic characterization of functional dendritic spines in the C. elegans motor circuit. Our approach demonstrates that C. elegans spines resemble those of mammalian neurons and offers a new in vivo paradigm for their exploration. This work is important because studies in C. elegans can accelerate our understanding of postsynaptic neurodevelopment.
In this paradigm, Dorsal D (DD) motor neurons initially synapse with ventral muscles but then switch their inputs to dorsal muscles. Using this developmental event of synaptic remodeling in a genetically tractable and transparent organism, we have uncovered new aspects of synapse elimination and how it can be coupled to the assembly of new boutons.
The Miller Lab has previously shown that neural activity, regulated by the DEG/ENaC cation channel, UNC-8, and calcineurin/TAX-6, drive disassembly of ventral GABAergic presynaptic terminals. Our new in vivo findings confirm that ENaC/UNC-8 promotes Ca++ transients during evoked transmission. Additional genetics and live-imaging experiments point to a downstream cellular mechanism in which presynaptic components are removed by a pathway resembling Activity-Dependent Bulk Endocytosis (ADBE). Our findings suggest that a native mechanism (ADBE) that normally functions to maintain neurotransmitter release at local synapses has been effectively repurposed, in this case, to dismantle presynaptic terminals.
Additional findings have provided a novel explanation for this unanticipated phenomenon. As we have identified that endogenous material from eliminating synapses can recycle to new dorsal boutons assembled distally. These coupling of synapse elimination and formation seems to be regulated by parallel pathways that differentially regulate the elimination of synaptic vesicle proteins and components of the active zone. Our observations suggest that synaptic disassembly is likely orchestrated by distinct cellular routes that ensure the specificity and fidelity of synaptic destruction and reassembly.
Finally, we present the systematic characterization of functional dendritic spines in the C. elegans motor circuit. Our approach demonstrates that C. elegans spines resemble those of mammalian neurons and offers a new in vivo paradigm for their exploration. We believe this work is important because studies in C. elegans can accelerate our understanding of neurodevelopment. | |
