Standard models for development and alteration of excitatory and inhibitory synapses posit that neurexins provide pre-synaptic cell adhesion molecules that bind heterophilically and with calcium-dependence to postsynaptic cell adhesion molecules to form trans-synaptic complexes that help to stabilize excitatory or inhibitory synapses [205]. Repertoires of diffusible entities enrich this picture. Neurexophilins provide soluble neurexin ligands that are expressed in neurons in a number of brain regions that also express NRXN3. Diffusible NRXN3 isoforms are expressed in brain regions that express several neuroligins and dystroglycan [222]. Conceivably, soluble neurexins and neurexophilins might diffuse to sites at which membrane-bound neuroligins and neurexins were localized. Enhancing ratios between diffusible and membrane bound NRXN3 isoforms in the CT/TT genotypes of rs8019381 might thus provide more diffused signaling in ways that could alter pruning, spreading and/or strength of synaptic contacts [223, 224].
