The neuron-specific intercellular adhesion molecule-5 (ICAM-5, telencephalin) is a member of the ICAM family of adhesion proteins. It has a complex structure with nine external immunoglobulin domains followed by a transmembrane and a cytoplasmic domain. The external part binds to beta1- and beta2-integrins and the matrix protein vitronectin, whereas its transmembrane domain binds to presenilins and the cytoplasmic domain to alpha-actinin and the ERM family of cytoplasmic proteins. In neurons it is confined to the soma and dendrites and it is enriched in dendritic filopodia with less expression in more mature dendritic spines. ICAM-5 strongly stimulates neurite outgrowth. ICAM-5 is cleaved by matrix metalloproteases upon activation of glutamate receptors or degraded through endocytosis resulting in increased spine maturation. Ablation of ICAM-5 expression increases functional synapse formation. The cleaved soluble fragment of ICAM-5 is immunosuppressive, which may be important in neuronal inflammatory diseases.