Claudia Lopes, McLean Hospital, Harvard Medical School
Conference: Society for Neuroscience 2018, San Diego, CA
Abstract Title: Cerebral Organoids as a New Way to Model ADHD Pathophysiology: A Look at Molecular, Cellular and Connectivity Deficits
Abstract: Attention deficit hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental disorder with a devastating impact on the quality of life of millions of children, adolescents and adults. While ADHD is thought to be highly heritable, its etiology is largely unknown is likely to involve a combination of environmental factors and the contribution of multiple genes defects. To understand the molecular underpinnings of ADHD, we hypothesize that 3D neuralized structures (organoids) derived from patient-specific induced pluripotent stem cells (iPSCs) can be used as a potential platform. In particular, the Prefrontal Cortex (PFC) is emerging to be of central relevance to the neural pathways of ADHD, as it connects extensively to sensory and motor cortices, as well as to the basal ganglia and cerebellum. These areas are intricately interconnected and modulated by a mesh of neurons that in ADHD display heavy deficits in dopaminergic and noradrenergic transmission. Thus, it is critical to understand the molecular influences modulating PFC’s function in order to develop novel medications for patients afflicted with the disorder. We have started to generate and characterize iPSC-derived cortical organoids from ADHD patients and healthy siblings controls to study the molecular and cellular differences in corticogenesis between diseased and control brains. Particularly, we propose that the root cause of the PFC’s smaller structure involves a limited progenitor pool and impaired radial migration. To achieve these long-term goals, we attempted to use our novel and non-viral reprogramming methods to generate high quality control and ADHD-iPSC lines, to optimize in vitro organoid generation, and then fusion organoid models. Our approach will facilitate examination of how disease risk is translated at the cellular and tissue levels through comparative studies of processes such as progenitor cell proliferation, migration and connectivity during development.