The neurexins and neuroligin are vital in guiding the activities of the molecular machinery. Complications like autism and cognitive disorders may occur due to the deletion of the two proteins. (Südhof, 2008). NRXN proteins are the presynaptic-most component of the tripartite bridge. As such, the exact similar effects on glutamatergic signaling as those described above for GluD1, GluD2, and Cbln2. However, multiple NRXN subtypes can participate in tripartite synaptic bridge structures, and NRXN deletion experiments reveal subtype-specific effects on AMPA and NMDA signals. Specifically, NRXN3 suppresses the postsynaptic AMPA signal, and NRXN1 enhances the postsynaptic NMDA signal (Südhof, 2008). Accordingly, NRXN3 deletion increases AMPA EPSCs, and NRXN1 deletion decreases NMDA EPSCs.
The neuronal circuit requires specific features and populations to function effectively. Diagram 1 below shows the emerging map of glutamate delta1 receptors in the forebrain. The alternative splice site “AS4” is responsible for NRXN-Cbln binding. Accordingly, one could expect deletion of the AS4 site to cause similar synaptic changes as those seen following NRXN deletion. Indeed, deletion of the AS4 site from either NRXN1 or NRXN3 replicates the NMDA or AMPA transmission changes described above, respectively. However, AS4 site sequences are heterologous between NRXN subtypes, and when the AS4 sites of NRXN1 and NRXN3 are experimentally swapped, the postsynaptic effects on AMPA and NMDA receptors exacted by NRXN1 and NRXN3 also switch.