Abstract

--- - "Background: Group 1 mGluRs induce dendritic spine remodeling, but the underlying molecular mechanisms remain uncharacterized. Results: -Actinin-4 regulates dendritic protrusion dynamics and morphogenesis and is required for the receptor-induced dynamic remodeling of dendritic protrusions. Conclusion: -Actinin-4 is a novel molecular effector of mGluR-dependent spine remodeling. Significance: mGluR signaling via actinins could contribute to synaptic plasticity and spine dysmorphogenesis in neurodevelopmental disorders." - Dendritic spines are dynamic, actin-rich protrusions in neurons that undergo remodeling during neuronal development and activity-dependent plasticity within the central nervous system. Although group 1 metabotropic glutamate receptors (mGluRs) are critical for spine remodeling under physiopathological conditions, the molecular components linking receptor activity to structural plasticity remain unknown. Here we identify a Ca2+-sensitive actin-binding protein, -actinin-4, as a novel group 1 mGluR-interacting partner that orchestrates spine dynamics and morphogenesis in primary neurons. Functional silencing of -actinin-4 abolished spine elongation and turnover stimulated by group 1 mGluRs despite intact surface receptor expression and downstream ERK1/2 signaling. This function of -actinin-4 in spine dynamics was underscored by gain-of-function phenotypes in untreated neurons. Here -actinin-4 induced spine head enlargement, a morphological change requiring the C-terminal domain of -actinin-4 that binds to CaMKII, an interaction we showed to be regulated by group 1 mGluR activation. Our data provide mechanistic insights into spine remodeling by metabotropic signaling and identify -actinin-4 as a critical effector of structural plasticity within neurons.