Role of L-type Calcium Channels in Human Interneuron Migration and Integration

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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. !