Mechanisms of Connectivity in Neuronal Development

The development of neuronal connectivity requires the careful orchestration of multiple cellular processes including the control of neuronal arborization and synapse formation or function. Defects in these processes during neuronal development will give rise to disorders of neuronal connectivity like autism. In the present work, we examine the genetic and epigenetic mechanisms that build the neuronal wiring of the developing brain. We use human stem cell-derived neurons to study neuronal arborization and function focusing on genetic and environmental risk factors of neurodevelopmental disorders that include autism and intellectual disability. Specifically, we focused on the contribution of the endomembrane, chromatin, and immune regulatory mechanisms to the development of human neuronal connectivity. To define the contribution of the endomembrane system we focus on RAB3GAP1- a gene that when mutated is associated with intellectual disability, autistic features, and reduced brain size. We found that RAB3GAP1 regulates neuronal morphogenesis, and that it might do so by regulating pathways relevant to autophagy. Autophagy is used to remove damaged cell proteins ensuring proper cell functioning. To define the contribution of chromatin regulatory mechanisms, we focused on the role of ASH1L a histone modifier in the control of neuronal function. We discovered that ASH1L might regulate the mTOR pathway, which is a major nexus of the regulation of neuronal connectivity. Finally, we interrogate how inflammation during neuronal development can lead to defects in neuronal development. We focused on the connection between inflammation and neuronal development by studying the effect of IL-17A exposure in human neurons. In summary, we establish human cellular models to interrogate the function of RAB3GAP1 (endomembrane), ASH1L (chromatin), and IL17A (immune) in neurodevelopmental disorders associated with autism and intellectual disability