Neurons communicate via synapses to allow normal brain functions such as cognition, memory formation, and learning. In these processes, synapses show plasticity and can be remodeled. Synapse formation is driven by synapse-organizing proteins that span the synaptic cleft to orchestrate the alignment of pre- and postsynaptic molecules. Recently, presynaptic α2δ proteins have been identified as crucial organizers of synapses by regulating axonal wiring, presynaptic differentiation, and postsynaptic receptor clustering. So far, α2δ proteins have been extensively studied as subunits of the voltage-gated calcium channels (CaV) complex, where they regulate channel trafficking and current kinetics. As presynaptic calcium influx is the critical trigger of neurotransmitter release, it is not surprising that mutations in α2δ proteins are found in patients with epilepsy, autism spectrum disorder, and schizophrenia. Considering its role as a synaptic organizer and based on previous experiments, we hypothesize that mutations in α2δ proteins may also mediate pathophysiological mechanisms independent of the channel complex. To test this, we performed immunocytochemistry experiments in neurons expressing a mutated α2δ-2 incapable of binding CaV and analyzed its ability to recruit postsynaptic GABAA receptors. Strikingly, channel-independent α2δ-2 still recruits postsynaptic GABAA receptors, shedding light on a previously unrecognized channel-independent synaptic organizing function. This leads us to hypothesize that interfering with the trans-synaptic function of α2δ proteins will allow us to modulate trans-synaptic signaling and synapse formation while leaving the presynaptic CaV signaling unaltered. Results from this ongoing project could open a new path for novel future treatment options for neurological and neuropsychiatric disorders.