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ICAM-5 is a negative regulator of dendritic spine maturation and facilitates the formation of filopodia. Its absence results in improved memory functions, but the mechanisms have remained poorly understood. Activation of NMDA receptors induces ICAM-5 ectodomain cleavage through a matrix metalloproteinase (MMP)-dependent pathway, which promotes spine maturation and synapse formation. Here, we report a novel, ICAM-5-dependent mechanism underlying spine maturation by regulating the dynamics and synaptic distribution of α-actinin. We found that GluN1 and ICAM-5 partially compete for the binding to α-actinin; deletion of the cytoplasmic tail of ICAM-5 or ablation of the gene resulted in increased association of GluN1 with α-actinin, whereas internalization of ICAM-5 peptide perturbed the GluN1/α-actinin interaction. NMDA treatment decreased α-actinin binding to ICAM-5, and increased the binding to GluN1. Proper synaptic distribution of α-actinin requires the ICAM-5 cytoplasmic domain, without which α-actinin tended to accumulate in filopodia, leading to F-actin reorganization. The results indicate that ICAM-5 retards spine maturation by preventing reorganization of the actin cytoskeleton, but NMDA receptor activation is sufficient to relieve the brake and promote the maturation of spines.

ICAM-5 affects spine maturation by regulation of NMDA receptor binding to α-actinin