A concerted neuron–astrocyte program declines in ageing and schizophrenia

Abstract

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 plasticity 1,2 —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.

References 185

1. 1.
   Cognitive impairment in schizophrenia: aetiology, pathophysiology, and treatment · 2023

   Corrected
2. 2.

   This reference’s wording can’t be shown under the paper’s licence.

   Not in our library10.1016/j.cger.2013.07.002

3. 3.

   This reference’s wording can’t be shown under the paper’s licence.

   Not in our library10.1038/nrg2612

4. 4.

   This reference’s wording can’t be shown under the paper’s licence.

   Not in our library10.1126/science.abe8457

5. 5.

   This reference’s wording can’t be shown under the paper’s licence.

   Not in our library10.1038/s41576-019-0130-6

6. 6.

   This reference’s wording can’t be shown under the paper’s licence.

   Not in our library10.1038/nn.4087

7. 7.

   This reference’s wording can’t be shown under the paper’s licence.

   Not in our library10.1016/j.stem.2023.01.010

8. 8.

   This reference’s wording can’t be shown under the paper’s licence.

   Not in our library10.1371/journal.pgen.1001276

9. 9.

   This reference’s wording can’t be shown under the paper’s licence.

   Not in our library10.1073/pnas.0506580102

10. 10.
    Identifying gene expression programs of cell-type identity and cellular activity with single-cell RNA-Seq · 2019

    No notice
11. 11.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1016/j.conb.2021.03.015

12. 12.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1111/febs.16540

13. 13.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1146/annurev-neuro-070918-050443

14. 14.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1126/science.adc9020

15. 15.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1002/glia.24191

16. 16.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1038/nature21029

17. 17.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1038/s41593-020-00783-4

18. 18.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1073/pnas.1534923100

19. 19.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1038/nn.3808

20. 20.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1038/s41586-020-3031-0

21. 21.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1016/s0959-4388(03)00041-2

22. 22.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1038/s41586-022-04434-5

23. 23.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1038/s41586-022-04556-w

24. 24.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1038/s41588-018-0129-5

25. 25.
    MAGMA: Generalized Gene-Set Analysis of GWAS Data · 2015

    No notice
26. 26.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1038/ng.3404

27. 27.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1093/hmg/ddn351

28. 28.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1038/ng.3725

29. 29.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1038/nature16549

30. 30.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1038/s41593-021-00847-z

31. 31.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1126/science.aat0473

32. 32.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1016/j.neuron.2017.09.056

33. 33.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1038/s41593-018-0325-8

34. 34.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1016/j.tins.2023.03.003

35. 35.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1016/j.plipres.2011.06.002

36. 36.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1523/jneurosci.0917-10.2010

37. 37.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1016/j.celrep.2022.111953

38. 38.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1016/j.biopsych.2012.01.002

39. 39.
    Brain ageing in schizophrenia: evidence from 26 international cohorts via the ENIGMA Schizophrenia consortium · 2022

    No notice
40. 40.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1093/schbul/sbm140

41. 41.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1001/archpsyc.57.1.65

42. 42.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1523/jneurosci.6410-09.2010

43. 43.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1016/j.neuroscience.2014.05.008

44. 44.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1176/appi.ajp.2017.16070814

45. 45.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1016/j.neurobiolaging.2018.09.003

46. 46.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1038/nrn3200

47. 47.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1177/1073858420945964

48. 48.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1093/schbul/sbw001

49. 49.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1001/jamapsychiatry.2015.1546

50. 50.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1001/jamapsychiatry.2021.0042

51. 51.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1016/b978-0-444-63639-3.00014-1

52. 52.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1001/archpsyc.1986.01800020020004

53. 53.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1176/appi.ajp.158.7.1105

54. 54.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1016/j.cell.2015.05.002

55. 55.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1038/s41592-023-01943-7

56. 56.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

57. 57.
    Accurate, scalable and integrative haplotype estimation · 2019

    No notice
58. 58.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1038/s41586-018-0321-x

59. 59.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1038/s41586-020-2430-6

60. 60.
    Contributions of common genetic variants to risk of schizophrenia among individuals of African and Latino ancestry · 2019

    No notice
61. 61.
    Genotype imputation using the Positional Burrows Wheeler Transform · 2020

    No notice
62. 62.
    High-coverage whole-genome sequencing of the expanded 1000 Genomes Project cohort including 602 trios · 2022

    No notice
63. 63.
    scPred: accurate supervised method for cell-type classification from single-cell RNA-seq data · 2019

    No notice
64. 64.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1016/j.cell.2019.05.031

65. 65.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

66. 66.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1101/2021.12.16.473007

67. 67.
    Array programming with NumPy · 2020

    No notice
68. 68.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.5281/zenodo.3509134

69. 69.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.25080/majora-92bf1922-00a

70. 70.
    SCANPY: large-scale single-cell gene expression data analysis · 2018

    No notice
71. 71.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

72. 72.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1016/j.cell.2018.07.028

73. 73.
    BBKNN: fast batch alignment of single cell transcriptomes · 2019

    No notice
74. 74.
    Clustering trees: a visualization for evaluating clusterings at multiple resolutions · 2018

    No notice
75. 75.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1038/s41586-019-1506-7

76. 76.
    Comparative cellular analysis of motor cortex in human, marmoset and mouse · 2021

    Corrected
77. 77.
    Human neocortical expansion involves glutamatergic neuron diversification · 2021

    Corrected
78. 78.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1038/s41597-022-01886-2

79. 79.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

80. 80.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

81. 81.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1038/nprot.2011.457

82. 82.
    Proteome profiling of cerebrospinal fluid reveals biomarker candidates for Parkinson’s disease · 2022

    No notice
83. 83.
    Diurnal rhythms in gene expression in the prefrontal cortex in schizophrenia · 2019

    Not checked
84. 84.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

85. 85.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

86. 86.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1038/ng1180

87. 87.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1038/75556

88. 88.
    The Gene Ontology knowledgebase in 2023 · 2023

    No notice
89. 89.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1093/bioinformatics/btr260

90. 90.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1016/j.cels.2015.12.004

91. 91.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1016/j.neuron.2019.05.002

92. 92.
    Astrocyte–neuron subproteomes and obsessive–compulsive disorder mechanisms · 2023

    No notice
93. 93.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1002/bies.10195

94. 94.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1016/j.mcn.2005.02.006

95. 95.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1523/jneurosci.2619-13.2013

96. 96.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1038/s41587-021-01066-4

97. 97.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1038/nmeth.4463

98. 98.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1038/s41596-020-0336-2

99. 99.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library10.1038/s41588-020-00721-x

100. 100.
     Trimmomatic: a flexible trimmer for Illumina sequence data · 2014

     No notice
101. 101.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1038/nmeth.1923

102. 102.
     Twelve years of SAMtools and BCFtools · 2021

     No notice
103. 103.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1016/j.cell.2013.03.035

104. 104.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1016/j.cell.2013.03.036

105. 105.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1093/nar/gkz1014

106. 106.
     The Eukaryotic Promoter Database: expansion of EPDnew and new promoter analysis tools · 2014

     No notice
107. 107.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1016/j.cels.2017.10.003

108. 108.
     Functional mapping and annotation of genetic associations with FUMA · 2017

     No notice
109. 109.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

110. 110.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1038/nature15393

111. 111.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1038/s41588-018-0081-4

112. 112.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1038/s41588-018-0269-7

113. 113.
     Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology · 2021

     Corrected
114. 114.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1038/s41588-021-00921-z

115. 115.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1038/s41588-018-0307-5

116. 116.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1038/s41588-019-0344-8

117. 117.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1038/s41588-021-00857-4

118. 118.
     Polygenic prediction of educational attainment within and between families from genome-wide association analyses in 3 million individuals · 2022

     No notice
119. 119.
     GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture · 2023

     No notice
120. 120.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1093/hmg/ddy271

121. 121.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1038/s41588-018-0152-6

122. 122.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1038/s41588-018-0333-3

123. 123.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1038/s41588-018-0151-7

124. 124.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1002/ajmg.b.32777

125. 125.
     International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci · 2019

     No notice
126. 126.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1038/s41588-018-0309-3

127. 127.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1038/ng.3552

128. 128.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1176/appi.ajp.2018.18070857

129. 129.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1038/ng.3760

130. 130.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1038/ng.3200

131. 131.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

132. 132.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

133. 133.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1126/science.abg8289

134. 134.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

135. 135.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

136. 136.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

137. 137.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

138. 138.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

139. 139.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1093/bioinformatics/btw313

140. 140.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1002/imt2.43

141. 141.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

142. 142.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

143. 143.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

144. 144.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

145. 145.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

146. 146.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

147. 147.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

148. 148.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

149. 149.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

150. 150.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

151. 151.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

152. 152.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

153. 153.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

154. 154.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

155. 155.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

156. 156.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

157. 157.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

158. 158.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

159. 159.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

160. 160.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

161. 161.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

162. 162.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

163. 163.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

164. 164.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

165. 165.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

166. 166.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

167. 167.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library

168. 168.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1126/science.aad6469

169. 169.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1038/s41598-017-17322-0

170. 170.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1038/s41586-022-04739-5

171. 171.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1016/j.neuron.2020.09.021

172. 172.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1101/2020.08.21.262097

173. 173.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1002/cbf.1600

174. 174.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1038/nature14186

175. 175.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1083/jcb.142.5.1279

176. 176.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1016/j.mcn.2016.10.005

177. 177.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.3389/fnsyn.2021.661681

178. 178.
     NGL-1/LRRC4C Deletion Moderately Suppresses Hippocampal Excitatory Synapse Development and Function in an Input-Independent Manner · 2019

     Not checked
179. 179.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1016/j.neuron.2013.06.049

180. 180.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1016/j.neuron.2013.06.029

181. 181.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1016/j.mcn.2018.07.002

182. 182.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1038/nrendo.2017.91

183. 183.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1016/j.biochi.2004.09.018

184. 184.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1016/j.neuron.2018.10.013

185. 185.

     This reference’s wording can’t be shown under the paper’s licence.

     Not in our library10.1038/s41398-019-0592-5

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