Alternative splicing plasticity of the neurexin family of synaptic adhesion molecules in human sensory neurons.

UNLABELLED: Plasticity within somatosensory circuits enables adaptations to environmental changes, however these can become maladaptive following injury and lead to chronic pain states. Presynaptic neurexins (Nrxns) are key organizers of synapse function that bind to a wide variety of postsynaptic proteins in a splice-isoform dependent manner to regulate synaptic connectivity, transmission and plasticity. Here we observed that NRXN alternative splicing at splice site 4 (SS4), an exon critical for synaptic function and long-term potentiation at synapses in the central nervous system, is plastic in human sensory neurons of the dorsal root ganglia (DRG). Taking a reverse translational approach, we used mouse models to understand what might regulate these splicing changes in DRG. We observed a shift to transcripts lacking this alternatively spliced exon for Nrxn1 and Nrxn3 in response to depolarization, but not sensitization with PGE 2 . Alternative splicing at SS4 was not altered by acute inflammatory pain but was reduced by central axotomy in vivo . We found that Nrxn alternative splicing patterns in DRG are dynamic during nervous system development, and vary between neurons of the DRG, spinal cord, and cortex in adult animals. Lastly, we observed that exon use at this site is conserved between species for Nrxn1α, but significantly different for all other isoforms. Thus, Nrxn alternative splicing at SS4 is plastic in human and mouse DRG neurons, which may influence somatosensory circuit wiring and synaptic function.

SIGNIFICANCE STATEMENT: The neurexin family of adhesion molecules act as key organizers of synaptic connectivity and function. These molecules undergo extensive alternative slicing to generate thousands of isoforms that can influence their interactions with diverse families of postsynaptic adhesion molecules. We found that alternative splicing at one of these key sites is altered in human somatosensory obtained from organ donors with damaged spinal grey matter. We then took a reverse translational approach in mouse model organisms to understand if Nrxn alternative splicing is plastic in peripheral somatosensory neurons of the dorsal root ganglia.