Most dendrite branches and a large fraction of dendritic spines in the adult rodent forebrain are stable for extended periods of time. Destabilization of these structures compromises brain function and is a major contributing factor to psychiatric and neurodegenerative diseases. Integrins are a class of transmembrane extracellular matrix receptors that function as αβ heterodimers and activate signaling cascades regulating the actin cytoskeleton. Here we identify integrin α3 as a key mediator of neuronal stability. Dendrites, dendritic spines, and synapses develop normally in mice with selective loss of integrin α3 in excitatory forebrain neurons, reaching their mature sizes and densities through postnatal day 21 (P21). However, by P42, integrin α3 mutant mice exhibit significant reductions in hippocampal dendrite arbor size and complexity, loss of dendritic spine and synapse densities, and impairments in hippocampal-dependent behavior. Furthermore, gene-dosage experiments demonstrate that integrin α3 interacts functionally with the Arg nonreceptor tyrosine kinase to activate p190RhoGAP, which inhibits RhoA GTPase and regulates hippocampal dendrite and synapse stability and mouse behavior. Together, our data support a fundamental role for integrin α3 in regulating dendrite arbor stability, synapse maintenance, and proper hippocampal function. In addition, these results provide a biochemical and structural explanation for the defects in long-term potentiation, learning, and memory reported previously in mice lacking integrin α3.
Pubmed ID: 23595732 RIS Download
Mesh terms: Age Factors | Analysis of Variance | Animals | Animals, Newborn | Basic Helix-Loop-Helix Transcription Factors | Cell Membrane | Dendrites | Dendritic Spines | Female | Gene Expression Regulation, Developmental | Green Fluorescent Proteins | Guanylate Kinases | Hippocampus | Immunoprecipitation | Integrin alpha3 | Lysine | Male | Membrane Proteins | Memory Disorders | Mice | Mice, Inbred C57BL | Mice, Transgenic | Models, Biological | Nerve Tissue Proteins | Neurons | Phosphopyruvate Hydratase | Recognition (Psychology) | Synapses | alpha-Fetoproteins | rhoA GTP-Binding Protein
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