Activation of NMDA receptors promotes dendritic spine development through MMP-mediated ICAM-5 cleavage.
Matrix metalloproteinase (MMP)-2 and -9 are pivotal in remodeling many tissues. However, their functions and candidate substrates for brain development are poorly characterized. Intercellular adhesion molecule-5 (ICAM-5; Telencephalin) is a neuronal adhesion molecule that regulates dendritic elongation and spine maturation. We find that ICAM-5 is cleaved from hippocampal neurons when the cells are treated with N-methyl-d-aspartic acid (NMDA) or alpha-amino-3-hydroxy-5-methylisoxazole-propionic acid (AMPA). The cleavage is blocked by MMP-2 and -9 inhibitors and small interfering RNAs. Newborn MMP-2- and MMP-9-deficient mice brains contain more full-length ICAM-5 than wild-type mice. NMDA receptor activation disrupts the actin cytoskeletal association of ICAM-5, which promotes its cleavage. ICAM-5 is mainly located in dendritic filopodia and immature thin spines. MMP inhibitors block the NMDA-induced cleavage of ICAM-5 more efficiently in dendritic shafts than in thin spines. ICAM-5 deficiency causes retraction of thin spine heads in response to NMDA stimulation. Soluble ICAM-5 promotes elongation of dendritic filopodia from wild-type neurons, but not from ICAM-5-deficient neurons. Thus, MMPs are important for ICAM-5-mediated dendritic spine development.
Tian
Li
L
Division of Biochemistry, Department of Biological and Environmental Sciences, Faculty of Biosciences, University of Helsinki, FIN-00014 Helsinki, Finland. li.tian@helsinki.fi
Stefanidakis
Michael
M
Ning
Lin
L
Van Lint
Philippe
P
Nyman-Huttunen
Henrietta
H
Libert
Claude
C
Itohara
Shigeyoshi
S
Mishina
Masayoshi
M
Rauvala
Heikki
H
Gahmberg
Carl G
CG
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D049229:Dendritic Spines / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
C504585:Icam5 protein, mouse; D061965:Matrix Metalloproteinase Inhibitors; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9