High-throughput single neuron resolution mapping of connecopathies in animal models of neurodevelopmental disorders

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The specific patterns of connectivity between the billions of neurons in our brain is widely believed to determine how we think and how we differ as individuals. Behavioural abnormalities associated with neurodevelopmental disorders including autism spectrum disorder (ASD), are likely to result from aberrant wiring of neural networks, but how this happens is unclear. We know from functional imaging studies that ASDs involve hypo-connectivity amongst distant brain areas. Moreover, many genes associated with ASDs govern molecular mechanisms of brain wiring. But how connectopathies manifest at the level of connectivity between individual neurons and brain areas is unknown, limiting the progress towards revealing the mechanistic causes of the disorder1. Here, we propose to apply state-of-the art barcoding based connectomics approaches2 to distinguish single neuron level mechanisms for aberrant connectivity in rodent models of monogenic forms of ASD3. We will also be using novel spatial transcriptomics approaches to analyze the brain-wide changes in gene expression in the ASD animal models.We expect this approach to be transformative for autism research since it will generate single cell resolution connectome and gene expression profiles of neurotypical and ASD brains and will pin down specifically which pathways and neurons are vulnerable to hypo-connectivity and miswiring. Second, our approach is fast and scalable. It will be adaptable to all brain areas and all neurodevelopmental disorders where an animal model is available. This will enable establishing a profile of connectopathies across different animal models of neurodevelopmental disorders such as Rett syndrome and Fragile X, revealing common and disparate structural deficits. Finally, our work will be a critical starting point for development of clinical interventions.