Building in vivo human neuronal models of neurodevelopmental diseases.

Neurodevelopmental disorders constitute a major class of brain disorders with a heavy societal burden and very few therapeutic options to this day, mainly because of our lack of knowledge of the underlying mechanisms at the levels of the affected neuronal circuits. Indeed it has remained almost impossible to study experimentally human defects at the neuronal level, given the relative inaccessibility of live human neuronal material. Our research group has pioneered in vivo models of human cortical neuron development, whereby human pluripotent stem cells can be are differentiated efficiently into pyramidal projection neurons, followed by xenotransplantation in the mouse cortex, where they display functional integration in the host neural circuits. In this proposal, we plan to use this unique model to study the formation and plasticity of cortical circuits involving human neurons affected by specific mutations leading to human neurodevelopmental disorders. This highly interdisciplinary project, with high impact for our understanding of human brain function and disease, will rely on the synergistic combination of human clinical genetics, pluripotent stem cell technologies, brain xenotransplantation, combined in a unique way with neuronal cell biology, electrophysiology and in vivo multiphoton microscopy.

Keywords:human brain development, cerebral cortex, pluripotent stem cells, neurodevelopment disorder, intellectual deficency

Disciplines:Developmental neuroscience