title: GluN3A expression restricts spine maturation via inhibition of GIT1/Rac1 signaling.
abstract: NMDA-type glutamate receptors (NMDARs) guide the activity-dependent remodeling of excitatory synapses and associated dendritic spines during critical periods of postnatal brain development. Whereas mature NMDARs composed of GluN1 and GluN2 subunits mediate synapse plasticity and promote spine growth and stabilization, juvenile NMDARs containing GluN3A subunits are thought to inhibit these processes via yet unknown mechanisms. Here, we report that GluN3A binds G protein-coupled receptor kinase-interacting protein (GIT1), a postsynaptic scaffold that assembles actin regulatory complexes, including the Rac1 guanine nucleotide exchange factor βPIX, to promote Rac1 activation in spines. Binding to GluN3A limits the synaptic localization of GIT1 and its ability to complex βPIX, leading to decreased Rac1 activation and reduced spine density and size in primary cultured neurons. Conversely, knocking out GluN3A favors the formation of GIT1/βPIX complexes and increases the activation of Rac1 and its main effector p21-activated kinase. We further show that binding of GluN3A to GIT1 is regulated by synaptic activity, a response that might restrict the negative regulatory effects of GluN3A on actin signaling to inactive synapses. Our results identify inhibition of Rac1/p21-activated kinase actin signaling pathways as an activity-dependent mechanism mediating the inhibitory effects of GluN3A on spine morphogenesis.
authors.affiliation: Cellular Neurobiology Laboratory, Centro de Investigación Médica Aplicada and Universidad de Navarra, 31008 Pamplona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Fiuza
authors.forename: Immaculada
authors.initials: I
authors.lastname: González-González
authors.forename: Isabel
authors.initials: I
authors.lastname: Pérez-Otaño
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D009024:Morphogenesis / Q000502:physiology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D064067:Rho Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013131:Spine / Q000166:cytology / Q000196:embryology*; D013569:Synapses / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D018797:Cell Cycle Proteins; C485648:Git1 protein, rat; D010750:Phosphoproteins; D016194:Receptors, N-Methyl-D-Aspartate; D064067:Rho Guanine Nucleotide Exchange Factors; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein
keywords: actin cytoskeleton; structural plasticity; synaptic refinement