gdnf and gfralpha1 promote formation of neuronal synapses by ligandinduced cell adhesion the establishment of synaptic connections requires precise alignment of pre and postsynaptic terminals the glial cell linederived neurotrophic factor gdnf receptor gfralpha1 is enriched at pre and postsynaptic compartments in hippocampal neurons suggesting that it has a function in synapse formation gdnf triggered transhomophilic binding between gfralpha1 molecules and cell adhesion between gfralpha1expressing cells this represents the first example of a cellcell interaction being mediated by a ligandinduced cell adhesion molecule licam in the presence of gdnf ectopic gfralpha1 induced localized presynaptic differentiation in hippocampal neurons as visualized by clustering of vesicular proteins and neurotransmitter transporters and by activitydependent vesicle recycling presynaptic differentiation induced by gdnf was markedly reduced in neurons lacking gfralpha1 gdnf mutant mice showed reduced synaptic localization of presynaptic proteins and a marked decrease in the density of presynaptic puncta indicating a role for gdnf signaling in hippocampal synaptogenesis in vivo we propose that gfralpha1 functions as a licam to establish precise synaptic contacts and induce presynaptic differentiation