Abstract
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 Ca(2+)-sensitive actin-binding protein, α-actinin-4, as a novel group 1 mGluR-interacting partner that orchestrates spine dynamics and morphogenesis in primary neurons. Functional silencing of α-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 α-actinin-4 in spine dynamics was underscored by gain-of-function phenotypes in untreated neurons. Here α-actinin-4 induced spine head enlargement, a morphological change requiring the C-terminal domain of α-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 α-actinin-4 as a critical effector of structural plasticity within neurons.
Highlights
Group 1 metabotropic glutamate receptors (mGluRs) induce dendritic spine remodeling, but the underlying molecular mechanisms remain uncharacterized
␣-actinin-4 induced spine head enlargement, a morphological change requiring the C-terminal domain of ␣-actinin-4 that binds to Calmodulin-dependent protein kinase II (CaMKII), an interaction we showed to be regulated by group 1 mGluR activation
We further demonstrate that ␣-actinin-4 plays a critical role in promoting protrusion motility and morphogenesis, the latter being a function dependent on the ␣-actinin-4 carboxyl terminus that mediates Ca2ϩ/Calmodulin-dependent protein kinase II (CaMKII) binding and show that this interaction is regulated by group 1 mGluRs
Summary
Group 1 mGluRs induce dendritic spine remodeling, but the underlying molecular mechanisms remain uncharacterized. 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. The mechanisms by which activity shapes synaptic circuits during excitatory synapse formation and elimination remain unclear, changes in spine dynamics have been shown to depend on modifications of the actin cytoskeleton [8, 9]. We further demonstrate that ␣-actinin-4 plays a critical role in promoting protrusion motility and morphogenesis, the latter being a function dependent on the ␣-actinin-4 carboxyl terminus that mediates Ca2ϩ/Calmodulin-dependent protein kinase II (CaMKII) binding and show that this interaction is regulated by group 1 mGluRs. Our findings provide molecular insights into effectors governing dendritic spine dynamics and identify novel mechanisms by which metabotropic signaling regulates structural plasticity
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