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

Fikri Birey¹, Min-Yin Li¹, Aaron Gordon², Mayuri V Thete¹, Alfredo M Valencia¹, Omer Revah¹, Anca M Paşca³, Daniel H Geschwind⁴, Sergiu P Paşca⁵

Affiliations

¹ Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Brain Organogenesis, Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305, USA.
² Program in Neurogenetics, Department of Neurology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pediatrics, Division of Neonatology, Stanford University, Stanford, CA 94305, USA.
⁴ Program in Neurogenetics, Department of Neurology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Center for Autism Research and Treatment, Semel Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Institute of Precision Health, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁵ Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Brain Organogenesis, Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305, USA. Electronic address: spasca@stanford.edu.

PMID: 34990580
DOI: 10.1016/j.stem.2021.11.011

Free article

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

Fikri Birey et al. Cell Stem Cell. 2022.

Free article

. 2022 Feb 3;29(2):248-264.e7.

doi: 10.1016/j.stem.2021.11.011. Epub 2022 Jan 5.

Authors

Fikri Birey¹, Min-Yin Li¹, Aaron Gordon², Mayuri V Thete¹, Alfredo M Valencia¹, Omer Revah¹, Anca M Paşca³, Daniel H Geschwind⁴, Sergiu P Paşca⁵

Affiliations

¹ Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Brain Organogenesis, Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305, USA.
² Program in Neurogenetics, Department of Neurology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pediatrics, Division of Neonatology, Stanford University, Stanford, CA 94305, USA.
⁴ Program in Neurogenetics, Department of Neurology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Center for Autism Research and Treatment, Semel Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Institute of Precision Health, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁵ Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Brain Organogenesis, Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305, USA. Electronic address: spasca@stanford.edu.

PMID: 34990580
DOI: 10.1016/j.stem.2021.11.011

Abstract

Defects in interneuron migration can disrupt the assembly of cortical circuits and lead to neuropsychiatric disease. Using forebrain assembloids derived by integration of cortical and ventral forebrain organoids, we have previously discovered a cortical interneuron migration defect in Timothy syndrome (TS), a severe neurodevelopmental disease caused by a mutation in the L-type calcium channel (LTCC) Ca_v1.2. Here, we find that acute pharmacological modulation of Ca_v1.2 can regulate the saltation length, but not the frequency, of interneuron migration in TS. Interestingly, the defect in saltation length is related to aberrant actomyosin and myosin light chain (MLC) phosphorylation, while the defect in saltation frequency is driven by enhanced γ-aminobutyric acid (GABA) sensitivity and can be restored by GABA-A receptor antagonism. Finally, we describe hypersynchronous hCS network activity in TS that is exacerbated by interneuron migration. Taken together, these studies reveal a complex role of LTCC function in human cortical interneuron migration and strategies to restore deficits in the context of disease.

Keywords: GABA; Timothy syndrome; assembloids; calcium; interneurons; organoids.

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Conflict of interest statement

Declaration of interests Stanford University holds patents and has provisional patent applications covering the generation of brain region-specific organoids and assembloids (F.B., A.M.P., and S.P.P.).

Comment in

Quickly moving too slowly: Interneuron migration in Timothy Syndrome.
Fernando MB, Brennand KJ. Fernando MB, et al. Cell Stem Cell. 2022 Feb 3;29(2):181-183. doi: 10.1016/j.stem.2022.01.004. Cell Stem Cell. 2022. PMID: 35120616

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

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

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