Abnormal assembly of neurons into circuits during corticogenesis is at the core of the behavioral deficits found in individuals with autism spectrum disorder (ASD). While recent progress has been made in identifying polygenic causes of ASD, how abnormal gene expression dynamically occurs during development to affect circuit assembly is essentially unaddressed. Moreover, the temporal dynamics of dysregulated gene expression during development remain unknown. Elucidating the cell-type specificity and developmental dynamics of dysregulated gene networks in ASD is, however, important to define the targets of potential therapeutic interventions.

Denis Jabaudon aims to identify the cell-type specificity and temporal dynamics of abnormal gene regulatory networks in a mouse model of ASD. Focusing on neocortical development in a 22q11.2 deletion syndrome mouse model (LgDel mice), Jabaudon proposes to investigate the cell-type- and developmental-stage-specific transcriptional programs of neocortical progenitors and their progeny and to identify abnormal developmental trajectories as neurons are wiring into circuits.

For this purpose, Jabaudon will take advantage of a technology his laboratory recently developed (FlashTag)¹, which, in combination with single-cell transcriptomics, allows labelling and real-time tracing of type-specific developmental transcriptional programs (Aim 1). Building on existing data in the laboratory, he and his colleagues will also examine transcriptional trajectories in corresponding populations of wild-type and LgDel cells in vivo to identify dynamically dysregulated gene networks with cell-type specificity (Aim 2). Finally, using a state-of-the-art single-cell connectomics approach, the team will link these abnormal programs with abnormal intracortical wiring (Aim 3), which is critical for multimodal integration and appears to be at the heart of the abnormal processing abilities in individuals with ASD and in mouse models of ASD.

Together, these experiments will provide a detailed, functional account of the molecular events linking the birth of neurons to their abnormal assembly into circuits and identifying potential developmental hot spots amendable to therapeutic interventions.