Interactions between Intercellular Adhesion Molecule-5 (ICAM-5) and β1 integrins regulate neuronal synapse formation.

ICAM-5 is a dendrite-specific adhesion molecule, which functions in both the immune and nervous systems. ICAM-5 is the only identified negative regulator for spine maturation so far. Shedding of ICAM-5 ectodomain leads to promoted spine maturation and enhanced 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 postsynaptic currents, an indicator of pre-synaptic release probability. Antibodies against ICAM-5 and β1 integrins altered spine maturation. Furthermore we found that β1 integrins serve as binding partners for ICAM-5. β1 integrins were immune precipitated with ICAM-5 from mouse brain and the binding region in ICAM-5 was localized to the two first Ig-domains. β1 integrins were juxtaposed to filopodia tips at the early stage of synaptic formation, but as synapses matured, β1 integrins covered the mushroom spines. Loss of β1 integrins from the pre-synaptic sites affected the morphology of the post-synaptic structures. ICAM-5 ectodomain cleavage decreased or increased respectively, when the interaction between ICAM-5 and β1 integrins was potentiated or weakened using antibodies. These results suggest that the interaction between ICAM-5 and β1 integrins plays an important role in formation of functional synapses.