(A) ICAM-5 cleavage by MMP-9 regulates dendritic spine maturation. ICAM-5 is expressed in immature dendritic protrusions during early development (A, left side). Cleavage by MMP-9 results in the loss of ICAM-5 from putative spines, an increase in ICAM-5 in dendritic shafts and a resultant shift to a mature phenotype (A, right side). (B) In the absence of MMP-9 (KO), ICAM-5 is expressed initially in immature dendritic protrusions (B, bottom panel left side), and is retained in these structures as development proceeds (B, bottom panel, ‘nascent spine’). Interestingly, we further found ICAM-5 retention in maturing dendritic protrusions by P28 (B, bottom panel, right side). This suggests a more complex relationship between ICAM-5 localization and synaptic maturation than previously envisioned. A possibility is that maturation effects may be mediated by soluble portions of ICAM-5 feeding back onto integrins in the dendritic spine.