DevATLAS: A novel tool to monitor the sequence of neural circuit development and study neurodevelopmental disorders

Abstract

Early postnatal brain development is the critical stage when the symptoms of many neurodevelopment disorders (NDDs) start manifesting. These functional deficits are often caused by abnormal neural circuit maturation without accompanying gross alteration to brain architecture, making it challenging to pinpoint disruptions in these NDD models. There is an urgent need for genetic tools to track the neural circuit maturation sequence on the whole brain level during the early postnatal period. One of the key driving factors of neural circuit maturation is neuronal activity. Our lab has developed DevATLAS, the Developmental Activation Timing-based Longitudinal Acquisition System, to overcome this challenge based on the immediate early gene Npas4 expression. Npas4 is selectively induced by neuronal activity, and its activation during development triggers activity-dependent synapse development, which is a critical step during the functional maturation of neural circuits. DevATLAS permanently labels neurons with tdTomato (tdT) as they are activated by neuronal activity to express Npas4. We demonstrate that DevATLAS captures the functional neural circuit maturation sequence across the whole brain during the early postnatal period. We also demonstrate that early environmental enrichment (EE) intervention can accelerate functional neural circuit development in the granule cells (GC) of the dentate gyrus (DG). Finally, we combine DevATLAS with the NDD model of Fragile-X Syndrome (FXS) and observe significant developmental perturbations in neural circuit maturation in multiple ASD-associated regions, including the dorsal striatum, primary motor cortex, medial prefrontal cortex, which can be associated with perturbed behaviors in juvenile FXS mice. Within the DG of FXS mice, we use DevATLAS to track perturbed neural circuit maturation with delayed emergence of contextual learning and memory with altered development of granule cell dendritic arbors and spines, as well as demonstrate how early EE can ameliorate. Our results indicate that DevATLAS can study neural circuit maturation in NDD models, enable researchers to gain an improved underlying NDD etiology, and ultimately help derive new therapeutic interventions to ameliorate NDD deficits.