The connectome of developing circuits in mouse models of autism

Proper brain function relies on the precise formation of neural circuits during development. Disruptions in this process can lead to neurodevelopmental disorders (NDDs) such as autism. Despite the importance of understanding circuit formation, direct data on how connections emerge postnatally has been limited. This is because until recently, comprehensively and completely mapping neuronal connections at any age was difficult if not impossible. Narayanan Kasthuri proposes to address this gap by leveraging advances in large volume serial electron microscopy (vEM) connectomics, synchrotron source X-ray imaging, and novel cell-type identification protocols. With these new tools, Kasthuri and his colleagues will ask how thalamic and parvalbumin neurons, well-studied circuits important for sensory processing, make the correct connections in the developing primary sensory cortex. They will examine how these same circuits are altered in two mouse models of NDDs (Fmr1 and Shank3), providing critical insights into the cellular and connection-level disruptions underlying these disorders. This project will generate unprecedented data on the formation and disruption of neural circuits during postnatal development. By identifying the precise time points, cell types and connections affected in the mouse models of autism, the Kasthuri lab will lay the groundwork for targeted interventions aimed at preventing or reversing circuit abnormalities in these disorders.