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. !

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH115012-03
Application #
9918982
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Panchision, David M
Project Start
2018-08-10
Project End
2023-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Stanford University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305