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Dissecting the molecular basis of human interneuron migration in forebrain assembloids from Timothy syndrome.
Birey, Fikri; Li, Min-Yin; Gordon, Aaron; Thete, Mayuri V; Valencia, Alfredo M; Revah, Omer; Pasca, Anca M; Geschwind, Daniel H; Pasca, Sergiu P.
Afiliação
  • Birey F; 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.
  • Li MY; 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.
  • Gordon A; Program in Neurogenetics, Department of Neurology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Thete MV; 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.
  • Valencia AM; 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.
  • Revah O; 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.
  • Pasca AM; 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.
  • Geschwind DH; 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 Inst
  • Pasca SP; 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.
Cell Stem Cell ; 29(2): 248-264.e7, 2022 02 03.
Article em En | MEDLINE | ID: mdl-34990580
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) Cav1.2. Here, we find that acute pharmacological modulation of Cav1.2 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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transtorno Autístico / Sindactilia Idioma: En Ano de publicação: 2022 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transtorno Autístico / Sindactilia Idioma: En Ano de publicação: 2022 Tipo de documento: Article