ABSTRACT Gene variants and mutations in voltage-gated L-type calcium channels (LTCCs) genes are among the most replicable findings in genetic studies of autism spectrum disorders, bipolar disorder and schizophrenia. The mechanisms by which these genetic events lead to disease are not currently known. Previous work has indicated that these LTCss play a critical role in cortical interneuron migration and functional integration into cortical circuits. Here, we propose to leverage a novel tridimensional (3D) neural differentiation of human induced pluripotent stem cells (hiPSC) that we developed to generate functional neural spheroids resembling the laminated excitatory cerebral cortex (pallial spheroids) and, separately, subpallial spheroids giving rise to cortical interneurons. Using state-of-the-art live imaging, transcriptional profiling, genetic-engineering, pharmacology and electrophysiological methods, we plan to assemble two-region human forebrain structures (pallial-excitatory/subpallial-inhibitory) and investigate the functional role of LTCCs mutations in migration and functional synaptic integration of cortical interneurons. !

NARRATIVE The goal of this proposal is to identify the molecular mechanisms leading to mental disorders in patients carrying mutations in a class of voltage-gated calcium channels. Gene variants and mutations in these key neuronal channels are among the most replicable findings in genetic studies of autism spectrum disorders, bipolar disorder and schizophrenia. However, the mechanisms by which these mutations lead to disease are not currently known. We propose to use cutting-edge stem cell and neuroscience technologies to generate in a dish from patients different subtypes of neurons present in the human cerebral cortex and use them to identify the abnormalities underlying disease in these subjects. The proposed project is relevant to public health because it has the potential to identify new therapeutic targets.