Exploring the neuropsychiatric spectrum using high-content functional analysis of single-cell signaling networks
| Autor: | Jordan M. Ramsey, Frieder Haenisch, Olya Mikova, Bonnie Auyeug, Jantine A. C. Broek, Tillmann Ruland, Simon Baron-Cohen, Jakub Tomasik, Nikolett Kabacs, Jason D. Cooper, Paula Suárez-Pinilla, Volker Arolt, Geertje F. van Rees, Santiago G. Lago, Benedicto Crespo-Facorro, Sabine Bahn |
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| Přispěvatelé: | Lago, Santiago G [0000-0002-3276-430X], van Rees, Geertje F [0000-0002-9431-0653], Haenisch, Frieder [0000-0001-7961-4467], Apollo - University of Cambridge Repository |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Cell signaling Bipolar Disorder Autism Spectrum Disorder signaling networks behavioral disciplines and activities Epitope spectrum functional analysis 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Antigen Single-cell analysis mental disorders drug targets Medicine Humans Bipolar disorder Molecular Biology Depressive Disorder Major business.industry high-content single-cell medicine.disease Psychiatry and Mental health neuropsychiatric disorders 030104 developmental biology Schizophrenia ex vivo Autism Major depressive disorder Female Single-Cell Analysis business Neuroscience 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Lago, S G, Tomasik, J, van Rees, G F, Ramsey, J M, Haenisch, F, Cooper, J D, Broek, J A, Suarez-Pinilla, P, Ruland, T, Auyeung, B, Mikova, O, Kabacs, N, Arolt, V, Baron-Cohen, S, Crespo-Facorro, B & Bahn, S 2018, ' Exploring the neuropsychiatric spectrum using high-content functional analysis of single-cell signaling networks ', Molecular Psychiatry, pp. 1-18 . https://doi.org/10.1038/s41380-018-0123-4 |
| DOI: | 10.1038/s41380-018-0123-4 |
| Popis: | Neuropsychiatric disorders overlap in symptoms and share genetic risk factors, challenging their current classification into distinct diagnostic categories. Novel cross-disorder approaches are needed to improve our understanding of the heterogeneous nature of neuropsychiatric diseases and overcome existing bottlenecks in their diagnosis and treatment. Here we employ high-content multi-parameter phospho-specific flow cytometry, fluorescent cell barcoding and automated sample preparation to characterize ex vivo signaling network responses (n = 1764) measured at the single-cell level in B and T lymphocytes across patients diagnosed with four major neuropsychiatric disorders: autism spectrum condition (ASC), bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ; n = 25 each), alongside matched healthy controls (n = 100). We identified 25 nodes (individual cell subtype–epitope–ligand combinations) significantly altered relative to the control group, with variable overlap between different neuropsychiatric diseases and heterogeneously expressed at the level of each individual patient. Reconstruction of the diagnostic categories from the altered nodes revealed an overlapping neuropsychiatric spectrum extending from MDD on one end, through BD and SCZ, to ASC on the other end. Network analysis showed that although the pathway structure of the epitopes was broadly preserved across the clinical groups, there were multiple discrete alterations in network connectivity, such as disconnections within the antigen/integrin receptor pathway and increased negative regulation within the Akt1 pathway in CD4+ T cells from ASC and SCZ patients, in addition to increased correlation of Stat1 (pY701) and Stat5 (pY694) responses in B cells from BD and MDD patients. Our results support the “dimensional” approach to neuropsychiatric disease classification and suggest potential novel drug targets along the neuropsychiatric spectrum. |
| Databáze: | OpenAIRE |
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