Abstract
ABSTRACTICAM-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.
Highlights
In the central nervous system, dendritic spines, the post-synaptic components of excitatory synapses, are small protrusions arising from the dendritic shafts
Localization of a-actinin is developmentally regulated To study the correlation of ICAM-5, GluN1 and a-actinin in spine maturation, we examined the distribution patterns of the proteins and the colocalization of them during development using immunofluorescent staining
A-actinin punctae almost overlapped with the actin-rich area along dendritic shafts, suggesting that a-actinin punctae mostly are located in spines
Summary
In the central nervous system, dendritic spines, the post-synaptic components of excitatory synapses, are small protrusions arising from the dendritic shafts. It is generally agreed that the flexible, filamentous nascent spines eventually turn into stable, mushroom-shaped spines as synapses mature. Modification of spine morphology is directly driven by polymerization and depolymerization of actin and a large number of proteins have been implicated in the regulation of actin reorganization underlying spine maturation (Ethell and Pasquale, 2005; Hotulainen and Hoogenraad, 2010). Abnormalities in spines are intimately associated with a multitude of neurological disorders.
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