Integrins Control Dendritic Spine Plasticity in Hippocampal Neurons throughNMDA Receptor and Ca2+/Calmodulin-Dependent Protein Kinase II-Mediated ActinReorganization

摘要

The formation of dendritic spines during development and their structural plasticity in the adult brain are critical aspects of synaptogenesis and synaptic plasticity. Many different factors and proteins have been shown to control dendritic spine development and remodeling (). The extracellular matrix (ECM) components and their cell surface receptors, integrins, have been found in the vicinity of synapses and shown to regulate synaptic efficacy and play an important role in long-term potentiation (href="#B2" rid="B2" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_807608466">Bahr et al., 1997; ; ; href="#B36" rid="B36" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_807608496">Lin et al., 2003; href="#B3" rid="B3" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_807608514">Bernard-Trifilo et al., 2005). Although molecular mechanisms by which integrins affect synaptic efficacy have begun to emerge, their role in structural plasticity is poorly understood. Here, we show that integrins are involved in spine remodeling in cultured hippocampal neurons. The treatment of 14 d in vitro hippocampal neurons with arginine–glycine–aspartate (RGD)-containing peptide, an established integrin ligand, induced elongation of existing dendritic spines and promoted formation of new filopodia. These effects were also accompanied by integrin-dependent actin reorganization and synapse remodeling, which were partially inhibited by function-blocking antibodiesagainst β1 and β3 integrins. This actin reorganization was blocked with theNMDA receptor (NMDAR) antagonist MK801[(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-iminehydrogen maleate]. The Ca²⁺/calmodulin-dependent protein kinase II (CaMKII)inhibitor KN93(N-[2-[N-(4-chlorocinnamyl)-N-methylaminomethyl]phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide)also suppressed RGD-induced actin reorganization and synapse remodeling. Our findings showthat integrins control ECM-mediated spine remodeling in hippocampal neurons throughNMDAR/CaMKII-dependent actin reorganization.