A concerted neuron-astrocyte program declines in ageing and schizophrenia

• 成果类型: Article
• 署名作者: Ling, Emi; Nemesh, James; Goldman, Melissa; Kamitaki, Nolan; Reed, Nora; Handsaker, Robert E.; Genovese, Giulio; Vogelgsang, Jonathan S.; Gerges, Sherif; Kashin, Seva; Ghosh, Sulagna; Esposito, John M.; Morris, Kiely; Meyer, Daniel; Lutservitz, Alyssa; Mullally, Christopher D.; Wysoker, Alec; Spina, Liv; Neumann, Anna; Hogan, Marina; Ichihara, Kiku; Berretta, Sabina; Mccarroll, Steven A.
• 署名单位: Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard Medical School; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; McLean Hospital; Harvard University; Harvard Medical School; Harvard University; Harvard Medical School
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4191
• DOI: 10.1038/s41586-024-07109-5
• 发表日期: 2024-03-21
• 关键词: genome-wide association; prefrontal cortex; transcription factors; spine density; risk loci; gene; brain; disease; determinants; heritability

摘要

Human brains vary across people and over time; such variation is not yet understood in cellular terms. Here we describe a relationship between people's cortical neurons and cortical astrocytes. We used single-nucleus RNA sequencing to analyse the prefrontal cortex of 191 human donors aged 22-97 years, including healthy individuals and people with schizophrenia. Latent-factor analysis of these data revealed that, in people whose cortical neurons more strongly expressed genes encoding synaptic components, cortical astrocytes more strongly expressed distinct genes with synaptic functions and genes for synthesizing cholesterol, an astrocyte-supplied component of synaptic membranes. We call this relationship the synaptic neuron and astrocyte program (SNAP). In schizophrenia and ageing-two conditions that involve declines in cognitive flexibility and plasticity1,2-cells divested from SNAP: astrocytes, glutamatergic (excitatory) neurons and GABAergic (inhibitory) neurons all showed reduced SNAP expression to corresponding degrees. The distinct astrocytic and neuronal components of SNAP both involved genes in which genetic risk factors for schizophrenia were strongly concentrated. SNAP, which varies quantitatively even among healthy people of similar age, may underlie many aspects of normal human interindividual differences and may be an important point of convergence for multiple kinds of pathophysiology. A synaptic neuron and astrocyte program (SNAP) varies among healthy humans, may shape interindividual differences in synapses and plasticity, and is undermined in schizophrenia and with advancing age.