Detangling synaptic complexity
Neuronal cells are responsible for reception, transmission, and integration of information in the central and peripheral nervous systems. They are morphologically and physiologically heterogeneous, and connected in a precise way through synapses, forming complex neuronal networks. Neurobiological research is trying to shed light into molecular mechanisms underlying proper formation of neuronal circuits. The scope of the EU-funded 'Deciphering the neurexin code in neuronal circuitry' (NRX CODE) project was to delineate the role of the surface receptors neurexins (NRXNs) in neuronal identity. NRXNs are cell-adhesion molecules known for their capacity to induce formation and organise neuronal synapses. Mutations in NRXN genes show strong correlation with neuropsychiatric disorders, including schizophrenia, autism and addiction. NRX CODE scientists wished to investigate the diversity of NRXNs created through alternative splicing at mRNA and protein levels. Using next-generation sequencing they revealed the content of NRXN mRNA transcripts in the adult mouse brain and demonstrated that NRXN repertoires correlate with cellular diversity of different brain areas. They observed that certain alternatively spliced sequences are responsible for the regulation of some NRXN variants at the mRNA level and thus gained important insight into the regulation of these genes. Additionally, NRX CODE scientists established selected reaction monitoring mass spectrometry assays, which allow relative and absolute quantification of different NRXN protein variants in different biological samples. This methodology capable of monitoring different NRXN splice variants at the protein level is an important step to further understand the role of NRX variants in vivo. Taken together, the experimental findings of the NRX CODE study provide fundamental insight into the diversification of NRXN gene by alternative splicing helping to understand the fundaments of neuronal diversity. Given the medical importance of NRXN gene mutations, the results and the tools of this study could be utilised for the clinical diagnosis of neuropsychiatric disorders.
