Aims: To investigate the function of the gene NRXN1 (Neurexin 1) which is one of the “high confidence” autism genes.
Background: Mutations in NRXN1 is one of about 100 high confidence rare genetic variants that has been associated with autism, although such rare variants are only found in less than 5% of autistic people. Nevertheless, NRXN1 can teach us about how genes affect neuronal development and function and alter brain function and structure to cause the strengths and challenges in perception, cognition and behaviour in autistic people. The puzzle of NRXN1 is that some people carry the mutation and develop autism, some carry it and develop a different psychiatric condition such as schizophrenia, some carry it and develop other neurodevelopmental conditions such as intellectual disability, and yet others carry the mutation and show no medical conditions or symptoms at all. This project is designed to understand why NRXN1 mutations can give rise to such diverse outcomes, and mechanistically, what this gene is doing. This project complements the ARC’s efforts in autism genetics that looks at other rare genetic variants, and looks at common genetic variants too.
Methods: We use a range of methods, starting with induced pluripotent stem cell lines derived neurons where the NRXN1 gene has been knocked out artificially or is mutated naturally, and then conducting experiments on these using electrophysiological recording, gene expression measures, and imaging of neuronal morphology. These experiments are being conducted in collaboration with Kings College London (KCL). Cambridge and KCL are part of an international consortium with their partners at University of Pennsylvania, who are using complementary methods, such as animal models, to investigate the same questions.
Results: These will be posted on the ARC website when they are available.
Importance: This project will teach us about the function of one ‘autism gene’, but this works in coordination with others (such as SHANK3) so we will gradually build up a picture of how NRXN1 works with its partner genes to regulate brain function and development.
Relevance: Currently this project is purely part of basic neuroscience and genetics. Whether it has translational relevance for drug development is beyond the scope of this project but this is certainly a possibility. As an aside, the ARC does not support drug therapies for autism per se, but is open to any therapy that targets unwanted symptoms (such as epilepsy, or gastro-intestinal pain), whether pharmacological or behavioural.
Funding: The Autism Research Trust, Templeton World Charitable Foundation, the Wellcome Trust