A single-cell genomic atlas for maturation of the human cerebellum during early childhood

被引:13
作者
Ament, Seth A. [1 ,2 ,3 ]
Cortes-Gutierrez, Marcia [1 ]
Herb, Brian R. [1 ,4 ]
Mocci, Evelina [1 ,5 ]
Colantuoni, Carlo [1 ,6 ,7 ]
McCarthy, Margaret M. [3 ,4 ]
机构
[1] Univ Maryland, Sch Med, Inst Genome Sci, Baltimore, MD 21201 USA
[2] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Dept Psychiat, Baltimore, MD 21201 USA
[3] Univ Maryland, Sch Med, UM MIND, Baltimore, MD 21201 USA
[4] Univ Maryland, Sch Med, Dept Pharmacol, Baltimore, MD 21201 USA
[5] Univ Maryland, Sch Nursing, Dept Pain Sci, Baltimore, MD USA
[6] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA
[7] Johns Hopkins Sch Med, Dept Neurosci, Baltimore, MD USA
关键词
ESTRADIOL SYNTHESIS; IMMUNE ACTIVATION; PROSTAGLANDIN-E2; DYSFUNCTION; ANNOTATION; VARIANTS; ONTOLOGY; BEHAVIOR; PACKAGE; MOUSE;
D O I
10.1126/scitranslmed.ade1283
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Inflammation early in life is a clinically established risk factor for autism spectrum disorders and schizophrenia, yet the impact of inflammation on human brain development is poorly understood. The cerebellum undergoes protracted postnatal maturation, making it especially susceptible to perturbations contributing to the risk of developing neurodevelopmental disorders. Here, using single-cell genomics of postmortem cerebellar brain samples, we characterized the postnatal development of cerebellar neurons and glia in 1- to 5-year-old children, comparing individuals who had died while experiencing inflammation with those who had died as a result of an accident. Our analyses revealed that inflammation and postnatal cerebellar maturation are associated with extensive, overlapping transcriptional changes primarily in two subtypes of inhibitory neurons: Purkinje neurons and Golgi neurons. Immunohistochemical analysis of a subset of these postmortem cerebellar samples revealed no change to Purkinje neuron soma size but evidence for increased activation of microglia in those children who had experienced inflammation. Maturation-associated and inflammation-associated gene expression changes included genes implicated in neurodevelopmental disorders. A gene regulatory network model integrating cell type-specific gene expression and chromatin accessibility identified seven temporally specific gene networks in Purkinje neurons and suggested that inflammation may be associated with the premature down-regulation of developmental gene expression programs.
引用
收藏
页数:15
相关论文
共 69 条
[51]   Emerging connections between cerebellar development, behaviour and complex brain disorders [J].
Sathyanesan, Aaron ;
Zhou, Joy ;
Scafidi, Joseph ;
Heck, Detlef H. ;
Sillitoe, Roy, V ;
Gallo, Vittorio .
NATURE REVIEWS NEUROSCIENCE, 2019, 20 (05) :298-313
[52]   The cerebellar cognitive affective syndrome [J].
Schmahmann, JD ;
Sherman, JC .
BRAIN, 1998, 121 :561-579
[53]  
Sepp M., 2021, BIORXIV, DOI [10.1101/2021.12.20.473443, DOI 10.1101/2021.12.20.473443]
[54]   Rare coding variants in ten genes confer substantial risk for schizophrenia [J].
Singh, Tarjinder ;
Poterba, Timothy ;
Curtis, David ;
Akil, Huda ;
Al Eissa, Mariam ;
Barchas, Jack D. ;
Bass, Nicholas ;
Bigdeli, Tim B. ;
Breen, Gerome ;
Bromet, Evelyn J. ;
Buckley, Peter F. ;
Bunney, William E. ;
Bybjerg-Grauholm, Jonas ;
Byerley, William F. ;
Chapman, Sinead B. ;
Chen, Wei J. ;
Churchhouse, Claire ;
Craddock, Nicholas ;
Cusick, Caroline M. ;
DeLisi, Lynn ;
Dodge, Sheila ;
Escamilla, Michael A. ;
Eskelinen, Saana ;
Fanous, Ayman H. ;
Faraone, Stephen, V ;
Fiorentino, Alessia ;
Francioli, Laurent ;
Gabriel, Stacey B. ;
Gage, Diane ;
Taliun, Sarah A. Gagliano ;
Ganna, Andrea ;
Genovese, Giulio ;
Glahn, David C. ;
Grove, Jakob ;
Hall, Mei-Hua ;
Hamalainen, Eija ;
Heyne, Henrike O. ;
Holi, Matti ;
Hougaard, David M. ;
Howrigan, Daniel P. ;
Huang, Hailiang ;
Hwu, Hai-Gwo ;
Kahn, Rene S. ;
Kang, Hyun Min ;
Karczewski, Konrad J. ;
Kirov, George ;
Knowles, James A. ;
Lee, Francis S. ;
Lehrer, Douglas S. ;
Lescai, Francesco .
NATURE, 2022, 604 (7906) :509-+
[55]   Common variants conferring risk of schizophrenia [J].
Stefansson, Hreinn ;
Ophoff, Roel A. ;
Steinberg, Stacy ;
Andreassen, Ole A. ;
Cichon, Sven ;
Rujescu, Dan ;
Werge, Thomas ;
Pietilainen, Olli P. H. ;
Mors, Ole ;
Mortensen, Preben B. ;
Sigurdsson, Engilbert ;
Gustafsson, Omar ;
Nyegaard, Mette ;
Tuulio-Henriksson, Annamari ;
Ingason, Andres ;
Hansen, Thomas ;
Suvisaari, Jaana ;
Lonnqvist, Jouko ;
Paunio, Tiina ;
Borglum, Anders D. ;
Hartmann, Annette ;
Fink-Jensen, Anders ;
Nordentoft, Merete ;
Hougaard, David ;
Norgaard-Pedersen, Bent ;
Bottcher, Yvonne ;
Olesen, Jes ;
Breuer, Rene ;
Moeller, Hans-Jurgen ;
Giegling, Ina ;
Rasmussen, Henrik B. ;
Timm, Sally ;
Mattheisen, Manuel ;
Bitter, Istvan ;
Rethelyi, Janos M. ;
Magnusdottir, Brynja B. ;
Sigmundsson, Thordur ;
Olason, Pall ;
Mason, Gisli ;
Gulcher, Jeffrey R. ;
Haraldsson, Magnus ;
Fossdal, Ragnheidur ;
Thorgeirsson, Thorgeir E. ;
Thorsteinsdottir, Unnur ;
Ruggeri, Mirella ;
Tosato, Sarah ;
Franke, Barbara ;
Strengman, Eric ;
Kiemeney, Lambertus A. ;
Melle, Ingrid .
NATURE, 2009, 460 (7256) :744-U99
[56]  
Stuart T., 2020, Cold Spring Harbor Laboratory, DOI [DOI 10.1101/2020.11.09.373613, 10.1101/2020.11.09.373613]
[57]   Cerebellum development during childhood and adolescence: A longitudinal morphometric MRI study [J].
Tiemeier, Henning ;
Lenroot, Rhoshel K. ;
Greenstein, Deanna K. ;
Tran, Lan ;
Pierson, Ronald ;
Giedd, Jay N. .
NEUROIMAGE, 2010, 49 (01) :63-70
[58]   Reduced Purkinje cell size in the cerebellar vermis of elderly patients with schizophrenia [J].
Tran, KD ;
Smutzer, GS ;
Doty, RL ;
Arnold, SE .
AMERICAN JOURNAL OF PSYCHIATRY, 1998, 155 (09) :1288-1290
[59]   Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice [J].
Tsai, Peter T. ;
Hull, Court ;
Chu, YunXiang ;
Greene-Colozzi, Emily ;
Sadowski, Abbey R. ;
Leech, Jarrett M. ;
Steinberg, Jason ;
Crawley, Jacqueline N. ;
Regehr, Wade G. ;
Sahin, Mustafa .
NATURE, 2012, 488 (7413) :647-+
[60]   Consensus Paper: Cerebellum and Social Cognition [J].
Van Overwalle, Frank ;
Manto, Mario ;
Cattaneo, Zaira ;
Clausi, Silvia ;
Ferrari, Chiara ;
Gabrieli, John D. E. ;
Guell, Xavier ;
Heleven, Elien ;
Lupo, Michela ;
Ma, Qianying ;
Michelutti, Marco ;
Olivito, Giusy ;
Pu, Min ;
Rice, Laura C. ;
Schmahmann, Jeremy D. ;
Siciliano, Libera ;
Sokolov, Arseny A. ;
Stoodley, Catherine J. ;
van Dun, Kim ;
Vandervert, Larry ;
Leggio, Maria .
CEREBELLUM, 2020, 19 (06) :833-868