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TCF4 Mutations Disrupt Synaptic Function Through Dysregulation of RIMBP2 in Patient-Derived Cortical Neurons.
Davis, Brittany A; Chen, Huei-Ying; Ye, Zengyou; Ostlund, Isaac; Tippani, Madhavi; Das, Debamitra; Sripathy, Srinidhi Rao; Wang, Yanhong; Martin, Jacqueline M; Shim, Gina; Panchwagh, Neel M; Moses, Rebecca L; Farinelli, Federica; Bohlen, Joseph F; Li, Meijie; Luikart, Bryan W; Jaffe, Andrew E; Maher, Brady J.
Afiliación
  • Davis BA; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
  • Chen HY; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland.
  • Ye Z; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland.
  • Ostlund I; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland.
  • Tippani M; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland.
  • Das D; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland.
  • Sripathy SR; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland.
  • Wang Y; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland.
  • Martin JM; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland.
  • Shim G; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland.
  • Panchwagh NM; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland.
  • Moses RL; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland.
  • Farinelli F; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland.
  • Bohlen JF; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland.
  • Li M; Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
  • Luikart BW; Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
  • Jaffe AE; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland; McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Me
  • Maher BJ; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Ba
Biol Psychiatry ; 95(7): 662-675, 2024 Apr 01.
Article en En | MEDLINE | ID: mdl-37573005
BACKGROUND: Genetic variation in the TCF4 (transcription factor 4) gene is associated with risk for a variety of developmental and psychiatric conditions, which includes a syndromic form of autism spectrum disorder called Pitt-Hopkins syndrome (PTHS). TCF4 encodes an activity-dependent transcription factor that is highly expressed during cortical development and in animal models has been shown to regulate various aspects of neuronal development and function. However, our understanding of how disease-causing mutations in TCF4 confer pathophysiology in a human context is lacking. METHODS: To model PTHS, we differentiated human cortical neurons from human induced pluripotent stem cells that were derived from patients with PTHS and neurotypical individuals. To identify pathophysiology and disease mechanisms, we assayed cortical neurons with whole-cell electrophysiology, Ca2+ imaging, multielectrode arrays, immunocytochemistry, and RNA sequencing. RESULTS: Cortical neurons derived from patients with TCF4 mutations showed deficits in spontaneous synaptic transmission, network excitability, and homeostatic plasticity. Transcriptomic analysis indicated that these phenotypes resulted in part from altered expression of genes involved in presynaptic neurotransmission and identified the presynaptic binding protein RIMBP2 as the most differentially expressed gene in PTHS neurons. Remarkably, TCF4-dependent deficits in spontaneous synaptic transmission and network excitability were rescued by increasing RIMBP2 expression in presynaptic neurons. CONCLUSIONS: Taken together, these results identify TCF4 as a critical transcriptional regulator of human synaptic development and plasticity and specifically identifies dysregulation of presynaptic function as an early pathophysiology in PTHS.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Madre Pluripotentes Inducidas / Trastorno del Espectro Autista / Discapacidad Intelectual Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Biol Psychiatry Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Madre Pluripotentes Inducidas / Trastorno del Espectro Autista / Discapacidad Intelectual Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Biol Psychiatry Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos