Interactions between ICAM-5 and β1 integrins regulate neuronal synapse formation

Intercellular adhesion molecule-5 (ICAM-5) is a dendrite-specific adhesion molecule, which functions in both the immune and nervous systems. ICAM-5 is the only negative regulator that has been identified for maturation of dendritic spines so far. Shedding of the ICAM-5 ectodomain promotes spine maturation and enhances synaptic activity. However, the mechanism by which ICAM-5 regulates spine development remains poorly understood. In this study, we found that ablation of ICAM5 expression resulted in a significant increase in the formation of synaptic contacts and the frequency of miniature excitatory post-synaptic currents, an indicator of pre-synaptic release probability. Antibodies against ICAM-5 and beta 1 integrins altered spine maturation. Furthermore, we found that beta 1 integrins serve as binding partners for ICAM-5. beta 1 integrins were immunoprecipitated with ICAM-5 from mouse brain and the binding region in ICAM-5 was localized to the two first Ig domains. beta 1 integrins were juxtaposed to filopodia tips at the early stage of synaptic formation, but as synapses matured, beta 1 integrins covered the mushroom spines. Loss of beta 1 integrins from the pre-synaptic sites affected the morphology of the post-synaptic structures. ICAM-5 ectodomain cleavage decreased or increased when the interaction between ICAM-5 and beta 1 integrins was potentiated or weakened, respectively, using antibodies. These results suggest that the interaction between ICAM-5 and beta 1 integrins is important in formation of functional synapses.