Contribution of neuroligin and neurexin alternative splicing to the establishment of enteric neuronal synaptic specificity

The enteric nervous system (ENS) is unique among components of the peripheral nervous system due to its complexity in structure and neurotransmitter phenotype diversity. In this complexity, the ENS resembles the central nervous system (CNS). Although the ENS is derived from the neural crest rather than the neural tube, similar mechanisms may generate complex connectivity in both the ENS and the CNS. Neuroligins and neurexins are cell adhesion molecules that participate in regulating CNS synaptogenesis. We investigated whether these molecules also play a role in establishing enteric synapses. We found that neuroligins and neurexins were expressed in mouse, rat, and human gut. Transcripts of both types of molecule were extensively spliced in the bowel during fetal and adult life. When transfected into non-neuronal cells, neuroligins and neurexins were sufficient to recruit, respectively, presynaptic and postsynaptic elements. Engineered soluble neurexin, which interferes with endogenous neurexin-neuroligin binding, inhibited enteric synapse formation/stabilization and recruitment of neurotransmitter receptors. Finally, we demonstrated that alternative splicing of neuroligin and neurexin contributes to ENS synaptic specificity. Some isoforms preferentially induced cholinergic synapses, whereas others promoted serotonergic synaptogenesis.<b>NEW & NOTEWORTHY</b> We found that neuroligins and neurexins play roles in establishing ENS synapses. Both are extensively spliced in the fetal and adult gut. When expressed in non-neuronal cells, both neuroligins and neurexins are sufficient to recruit, respectively, presynaptic and postsynaptic elements. Soluble neurexin inhibits enteric synapse formation and recruitment of neurotransmitter receptors by interfering with endogenous neurexin/neuroligin binding. The neurexin/neuroligin splice code contributes physiologically to ENS synaptic specificity, promoting for example, cholinergic or serotonergic synaptogenesis.