The coordinated activity of the nervous system depends on the accurate formation of synaptic connections across distinct brain regions. The establishment of long-range, structure-spanning circuits requires molecular systems capable of guiding synapse formation with both spatial and functional precision. Among these, trans-synaptic adhesion molecules play a central role, mediating recognition and stabilization between neurons and their targets. In particular, ligand-induced cell adhesion molecules (LiCAMs) have emerged as unique mediators that combine the signaling versatility of diffusible factors with the spatial specificity of membrane-bound molecules. One such ligand, glial cell line-derived neurotrophic factor (GDNF), orchestrates trans-synaptic assembly through interaction with its receptor GFRα1, expressed at both pre- and postsynaptic sites. Here, we explore the molecular mechanisms by which GFRα-family receptors contribute to the formation of GDNF-mediated trans-synaptic complexes, proposing a role for this signaling in bridging neural circuits across anatomically distinct brain areas.