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

Area of Science:

• Neuroscience
• Cell Biology
• Molecular Biology

Background:

• Intercellular Adhesion Molecule 5 (ICAM-5) is a known regulator of dendritic spine maturation and filopodia formation.
• While ICAM-5 absence improves memory, the underlying molecular mechanisms are not fully understood.
• NMDA receptor activation triggers ICAM-5 cleavage, promoting spine maturation.

Purpose of the Study:

• To elucidate the novel ICAM-5-dependent mechanism regulating spine maturation via α-actinin dynamics.
• To investigate the interaction between ICAM-5, GluN1, and α-actinin during spine maturation.

Main Methods:

• Investigated ICAM-5 and GluN1 binding to α-actinin using genetic manipulations (cytoplasmic tail deletion, gene ablation).
• Examined the effect of ICAM-5 peptide internalization on protein interactions.
• Analyzed changes in α-actinin binding to ICAM-5 and GluN1 following NMDA receptor activation.
• Observed α-actinin distribution and F-actin reorganization in response to ICAM-5 cytoplasmic domain presence or absence.

Main Results:

• ICAM-5 and GluN1 compete for α-actinin binding.
• ICAM-5 cytoplasmic tail deletion or gene ablation increases GluN1-α-actinin association.
• NMDA receptor activation reduces α-actinin binding to ICAM-5 and enhances binding to GluN1.
• The ICAM-5 cytoplasmic domain is crucial for proper synaptic α-actinin distribution; its absence leads to α-actinin accumulation in filopodia and F-actin reorganization.

Conclusions:

• ICAM-5 acts as a brake on spine maturation by inhibiting actin cytoskeleton reorganization.
• NMDA receptor activation overcomes ICAM-5's inhibitory effect, promoting spine maturation.
• Regulation of α-actinin dynamics and synaptic distribution by ICAM-5 is a key mechanism in controlling spine maturation.