BDNF-dependent nano-organization of Neogenin and the WAVE regulatory complex promotes actin remodeling in dendritic spines
Belal Shohayeb,
Kai Sempert,
Tristan P. Wallis,
Frédéric A. Meunier,
Nela Durisic,
Elizabeth A. O'Brien,
Cecilia Flores,
Helen M. Cooper
Affiliations
Belal Shohayeb
Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
Kai Sempert
Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
Tristan P. Wallis
Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia; Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
Frédéric A. Meunier
Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia; Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia; The School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia
Nela Durisic
Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
Elizabeth A. O'Brien
Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
Cecilia Flores
Department of Psychiatry and Department of Neurology and Neurosurgery, McGill University, Montréal, Canada; Douglas Mental Health University Institute, Montréal, Canada; Ludmer Centre for Neuroinformatics & Mental Health, McGill University, Montréal, Canada
Helen M. Cooper
Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia; Corresponding author
Summary: Synaptic structural plasticity, the expansion of dendritic spines in response to synaptic stimulation, is essential for experience-dependent plasticity and is driven by branched actin polymerization. The WAVE regulatory complex (WRC) is confined to nanodomains at the postsynaptic membrane where it catalyzes actin polymerization. As the netrin/RGM receptor Neogenin is a critical regulator of the WRC, its nanoscale organization may be an important determinant of WRC nanoarchitecture and function. Using super-resolution microscopy, we reveal that Neogenin is highly organized on the spine membrane at the nanoscale level. We show that Neogenin binding to the WRC promotes co-clustering into nanodomains in response to brain-derived neurotrophic factor (BDNF), indicating that nanoclustering occurs in response to synaptic stimulation. Disruption of Neogenin/WRC binding not only prevents BDNF-mediated actin remodeling but also inhibits BDNF-induced calcium signaling. We conclude that the assembly of Neogenin/WRC nanodomains is a prerequisite for BDNF-mediated structural and synaptic plasticity.
