TY - JOUR
T1 - A single-cell genomic atlas for maturation of the human cerebellum during early childhood
AU - Ament, Seth A.
AU - Cortes-Gutierrez, Marcia
AU - Herb, Brian R.
AU - Mocci, Evelina
AU - Colantuoni, Carlo
AU - McCarthy, Margaret M.
N1 - Publisher Copyright:
Copyright © 2023 The Authors, some rights reserved;
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85176508638&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85176508638&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.ade1283
DO - 10.1126/scitranslmed.ade1283
M3 - Article
C2 - 37824600
AN - SCOPUS:85176508638
SN - 1946-6234
VL - 15
JO - Science translational medicine
JF - Science translational medicine
IS - 721
M1 - 1283
ER -