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¹ Division of Biochemistry, Department of Biological and Environmental Sciences, Faculty of Biosciences, and ² Neuroscience Center, University of Helsinki, FIN-00014 Helsinki, Finland
³ Department for Molecular Biomedical Research, Flanders Interuniversity Institute for Biotechnology and Ghent University, B-9052 Ghent (Zwijnaarde), Belgium
⁴ Laboratory of Behavioral Genetics, Institute of Physical and Chemical Research, Brain Science Institute, Wako, 351-0198, Japan
⁵ Department of Molecular Neurobiology and Pharmacology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, 113-0033, Japan

Correspondence to Li Tian: li.tian{at}helsinki.fi

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 -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.

M. Stefanidakis and L. Ning contributed equally to this paper.

M. Stefanidakis's present address is Department of Pathology, Harvard Medical School, Brigham and Women's Hospital, Center for Excellence in Vascular Biology, Boston, MA 02115.

Abbreviations used in this paper: AMPA, -amino-3-hydroxy-5-methylisoxazole-propionic acid; CAM, cell adhesion molecule; CTF, C-terminal fragment; DIV, day in vitro; DNQX, 6,7,-dinitroquinoxaline-2,3 (1H,4H)-dione; ICAM, intercellular adhesion molecule; LTP, long-term potentiation; MALDI-TOF, matrix-assisted laser desorption/ionization–time of flight; MAP, microtubule-associated protein; MMP, matrix metalloproteinase; NMDA, N-methyl-D-aspartic acid; NR, NMDA receptor; NTF, N-terminal fragment; PSD, postsynaptic density; sICAM-5, soluble ICAM-5; WT, wild type.

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