July 11, 2013. A new study published July 3 in Cell finds that alternative splicing of neurexin 3, a presynaptic cell adhesion molecule, can influence synapse function and plasticity on the postsynaptic side. Led by Thomas Südhof of Stanford University, Palo Alto, California, the study is the first to design a knock-in mouse that constitutively expresses a specific splice variant—in this case, one containing the alternatively spliced sequence #4 (SS4)—to probe its role at the synapse. This manipulation decreased signals through the AMPA subtype of glutamate receptor on the postsynaptic side and interfered with long-term potentiation (LTP) there, – something that indicates presynaptic “permission” is necessary for postsynaptic plasticity.
The findings may offer insight into the workings of neurexin 1, whose gene has been implicated in schizophrenia and autism (see SRF related news story). With three neurexin genes in humans, each with five different splice sites, thousands of different neurexin variants are possible, and they don’t all bind to the same postsynaptic molecules, which include neuroligins and leucine-rich repeat transmembrane proteins (LRRTMs) (see SRF related news story). These postsynaptic partners then interact with a variety of other molecules responsible for getting signals from one neuron to the next. SS4-containing neurexins selectively bind to neuroligin 1 (Siddiqui et al., 2010), and this partnership could result in the change in AMPA receptor trafficking and stabilization found in the new study.
Splice variants have been suspected in schizophrenia before, and transcriptome profiling now enables researchers to track their expression comprehensively (see SRF related news story). By finding that a splice variant can reshape synapse function, the new study affirms the importance of these variants and suggests that, for schizophrenia—often touted as a disorder of disconnectivity—the disconnect may lies not so much in the physical contact between two neurons, but in the workings of their synaptic machinery.—Michele Solis.
Aoto J, Martinelli DC, Malenka RC, Tabuchi K, Südhof TC. Presynaptic Neurexin-3 Alternative Splicing trans-Synaptically Controls Postsynaptic AMPA Receptor Trafficking. Cell. 2013 Jul 3;154(1):75-88. Abstract