Your browser doesn't support javascript.
loading
Neuronal defects in a human cellular model of 22q11.2 deletion syndrome.
Khan, Themasap A; Revah, Omer; Gordon, Aaron; Yoon, Se-Jin; Krawisz, Anna K; Goold, Carleton; Sun, Yishan; Kim, Chul Hoon; Tian, Yuan; Li, Min-Yin; Schaepe, Julia M; Ikeda, Kazuya; Amin, Neal D; Sakai, Noriaki; Yazawa, Masayuki; Kushan, Leila; Nishino, Seiji; Porteus, Matthew H; Rapoport, Judith L; Bernstein, Jonathan A; O'Hara, Ruth; Bearden, Carrie E; Hallmayer, Joachim F; Huguenard, John R; Geschwind, Daniel H; Dolmetsch, Ricardo E; Pasca, Sergiu P.
Afiliación
  • Khan TA; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
  • Revah O; Program in Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA.
  • Gordon A; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
  • Yoon SJ; Program in Neurogenetics, Department of Neurology, University of California Los Angeles, Los Angeles, CA, USA.
  • Krawisz AK; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
  • Goold C; Department of Neurobiology, Stanford University, Stanford, CA, USA.
  • Sun Y; Division of Cardiology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
  • Kim CH; Department of Neurobiology, Stanford University, Stanford, CA, USA.
  • Tian Y; Department of Neurobiology, Stanford University, Stanford, CA, USA.
  • Li MY; Department of Neurobiology, Stanford University, Stanford, CA, USA.
  • Schaepe JM; Department of Pharmacology, Yonsei University College of Medicine, Seoul, Republic of Korea.
  • Ikeda K; Program in Neurogenetics, Department of Neurology, University of California Los Angeles, Los Angeles, CA, USA.
  • Amin ND; Interdepartmental PhD Program in Bioinformatics, University of California Los Angeles, Los Angeles, CA, USA.
  • Sakai N; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
  • Yazawa M; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
  • Kushan L; Department of Pediatrics, Stanford University, Stanford, CA, USA.
  • Nishino S; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
  • Porteus MH; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
  • Rapoport JL; Department of Neurobiology, Stanford University, Stanford, CA, USA.
  • Bernstein JA; Columbia Stem Cell Initiative, Department of Rehabilitation and Regenerative Medicine, Department of Molecular Pharmacology and Therapeutics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • O'Hara R; Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA, USA.
  • Bearden CE; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
  • Hallmayer JF; Department of Pediatrics, Stanford University, Stanford, CA, USA.
  • Huguenard JR; National Institute of Mental Health, Child Psychiatry Branch, Bethesda, MD, USA.
  • Geschwind DH; Department of Pediatrics, Stanford University, Stanford, CA, USA.
  • Dolmetsch RE; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
  • Pasca SP; Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA, USA.
Nat Med ; 26(12): 1888-1898, 2020 12.
Article en En | MEDLINE | ID: mdl-32989314
ABSTRACT
22q11.2 deletion syndrome (22q11DS) is a highly penetrant and common genetic cause of neuropsychiatric disease. Here we generated induced pluripotent stem cells from 15 individuals with 22q11DS and 15 control individuals and differentiated them into three-dimensional (3D) cerebral cortical organoids. Transcriptional profiling across 100 days showed high reliability of differentiation and revealed changes in neuronal excitability-related genes. Using electrophysiology and live imaging, we identified defects in spontaneous neuronal activity and calcium signaling in both organoid- and 2D-derived cortical neurons. The calcium deficit was related to resting membrane potential changes that led to abnormal inactivation of voltage-gated calcium channels. Heterozygous loss of DGCR8 recapitulated the excitability and calcium phenotypes and its overexpression rescued these defects. Moreover, the 22q11DS calcium abnormality could also be restored by application of antipsychotics. Taken together, our study illustrates how stem cell derived models can be used to uncover and rescue cellular phenotypes associated with genetic forms of neuropsychiatric disease.
Asunto(s)
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Corteza Cerebral / Señalización del Calcio / Síndrome de DiGeorge / Neuronas Tipo de estudio: Prognostic_studies Límite: Adult / Female / Humans / Male Idioma: En Revista: Nat Med Asunto de la revista: BIOLOGIA MOLECULAR / MEDICINA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Corteza Cerebral / Señalización del Calcio / Síndrome de DiGeorge / Neuronas Tipo de estudio: Prognostic_studies Límite: Adult / Female / Humans / Male Idioma: En Revista: Nat Med Asunto de la revista: BIOLOGIA MOLECULAR / MEDICINA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos