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bioRxiv · 10.1101/2021.06.14.448277

Dissecting the molecular basis of human interneuron migrationin forebrain assembloids from Timothy syndrome

Birey, F.·Li, M.-Y.·Gordon, A.·Thete, M.·Valencia, A. M.·Revah, O.·Pasca, A. M.·Geschwind, D. H.·Pasca, S. P.
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Abstract

Defects in interneuron migration during forebrain development can disrupt the assembly of cortical circuits and have been associated with neuropsychiatric disease. The molecular and cellular bases of such deficits have been particularly difficult to study in humans due to limited access to functional forebrain tissue from patients. We previously developed a human forebrain assembloid model of Timothy Syndrome (TS), caused by a gain-of-function mutation in CACNA1C which encodes the L-type calcium channel (LTCC) Cav1.2. By functionally integrating human induced pluripotent stem cell (hiPSC)-derived organoids resembling the dorsal and ventral forebrain from patients and control individuals, we uncovered that migration is disrupted in TS cortical interneurons. Here, we dissect the molecular underpinnings of this phenotype and report that acute pharmacological modulation of Cav1.2 can rescue the saltation length but not the saltation frequency of TS migrating interneurons. Furthermore, we find that the defect in saltation length in TS interneurons is associated with aberrant actomyosin function and is rescued by pharmacological modulation of MLC phosphorylation, whereas the saltation frequency phenotype in TS interneurons is driven by enhanced GABA sensitivity and can be restored by GABA receptor antagonism. Overall, these findings uncover multi-faceted roles of LTCC function in human cortical interneuron migration in the context of disease and suggest new strategies to restore interneuron migration deficits.

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Birey, F., Li, M.-Y., Gordon, A., Thete, M., Valencia, A. M., Revah, O., Pasca, A. M., Geschwind, D. H., Pasca, S. P.. 2021-06-15. Dissecting the molecular basis of human interneuron migrationin forebrain assembloids from Timothy syndrome. https://doi.org/10.1101/2021.06.14.448277

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