COMPARATIVE MOLECULAR CONNECTOMICS TO UNCOVER THE IMPACT OF MUTATIONS IN AUTISM RISK GENES<EM > IN VIVO</EM>

Autism Spectrum Condition (ASC) is a neurodevelopmental disorder with diverse clinical presentations and substantial genetic heterogeneity. It is characterized by restricted interests, repetitive behaviors, and differences in social communication, affecting more than 60 million individuals worldwide. With an estimated heritability of ~80%, autism has a strong genetic basis, and over 100 ASC-associated genes have been identified. Despite their diverse functions, evidence suggests that mutations in these genes converge on shared molecular pathways underlying neurodevelopmental differences in ASC. However, it remains largely unclear how distinct genetic risk factors shape neuronal gene expression profiles, cellular subtype identity, and circuit connectivity during brain development. Owing to its heterogeneous genetic architecture, ASC provides a valuable framework for studying the neurogenetic principles of brain development, organization, and function. In recent years, viral barcoding combined with neuronal tracing has emerged as high-throughput approach to study synaptic connectivity, overcoming key limitations of traditional methods such as electrophysiology and electron microscopy. Here, we will apply this strategy to investigate both long-range and local connectivity in the prefrontal cortex (PFC), a brain region critical for higher-order cognitive functions and frequently implicated in neurodevelopmental conditions including autism. By comparing in vivo systems with different genetic perturbations, we aim to elucidate how mutations in autism-associated genes influence molecular, cellular, and circuit-level processes in the PFC during brain development.