Collaborative Research: Molecular mechanisms of dendrite development, maintenance and plasticity: in vivo single-neuron analysis in C. elegans

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Brain development involves the formation and fine-tuning of complex networks of connections between nerve cells. These connections occur at specialized sites of nerve cell contact, often formed on thorn-like structures (called spines) that protrude from the nerve cells. Precisely-controlled structural changes in spines are important for proper learning and memory. Some neuro-developmental disorders are the result of improper spine outgrowth, or a failure to properly maintain spines. These dysfunctions result in abnormalities in nerve cell communication that decrease learning and memory performance. Preliminary work for the present project has shown that connections between some nerve cells in the nematode worm Caenorhabditis elegans have spine-like structures, similar to those in the human brain. This project will investigate the mechanisms by which spines are formed during normal development, and maintained throughout life. The research uses C. elegans worms because of the powerful genetic tools developed in this species for identifying and understanding molecular pathways that control basic cell functions. By applying these tools to the mechanisms underlying spine outgrowth and maintenance, we expect to gain critical novel insights into the requirements for healthy brain function. Important insights into neurodevelopmental disorders may also be provided. This research project will also support the training of future scientists by providing mentored research experiences for undergraduate and graduate students, as well as local high school teachers. Recruitment for these activities will emphasize participants from under-represented groups in science.Most excitatory synapses in the mammalian brain occur at dendritic spines, which are small actin-rich membrane protrusions that house neurotransmitter receptors and other signaling machinery. Spines are essential structures in synaptic connectivity and plasticity, and underlie important processes of learning and memory. Despite recent progress in defining molecular mechanisms that regulate spine morphological changes, many questions about the basic biology of spine formation, maintenance and plasticity remain unanswered. The role of the extracellular matrix (ECM) in regulating spine development and maintenance is particularly poorly understood. The present studies will employ genetic tools available in the nematode worm Caenorhabditis elegans to identify and characterize molecular pathways involved in synapse development and plasticity. Preliminary work revealed that excitatory synaptic contacts onto C. elegans GABAergic neurons occur at spine-like protrusions. This collaborative project, incorporating expertise from the Lemons, Francis and B'nard labs, will investigate ECM-mediated mechanisms for guiding dendrite development and dynamics, as well as applying unbiased forward genetic screening to uncover novel cellular and molecular pathways that regulate dendritic spines in vivo.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.