Disease-specific differences in gene expression, mitochondrial function and mitochondria-endoplasmic reticulum interactions in iPSC-derived cerebral organoids and cortical neurons in schizophrenia and bipolar disorder

Annie Kathuria; Kara Lopez-Lengowski; Donna McPhie; Bruce M Cohen; Rakesh Karmacharya

doi:10.1007/s44192-023-00031-8

Disease-specific differences in gene expression, mitochondrial function and mitochondria-endoplasmic reticulum interactions in iPSC-derived cerebral organoids and cortical neurons in schizophrenia and bipolar disorder

Discov Ment Health. 2023;3(1):8. doi: 10.1007/s44192-023-00031-8. Epub 2023 Mar 9.

Authors

Annie Kathuria^{1

2

3}, Kara Lopez-Lengowski^{1

2}, Donna McPhie^{3

4}, Bruce M Cohen^{3

4}, Rakesh Karmacharya^{1

2

3

4

5

6

7}

Affiliations

¹ Center for Genomic Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114 USA.
² Chemical Biology Program, Broad Institute of MIT & Harvard, Cambridge, MA USA.
³ Department of Psychiatry, Harvard Medical School, Boston, MA USA.
⁴ Schizophrenia and Bipolar Disorder Program, McLean Hospital, Belmont, MA USA.
⁵ Program in Neuroscience, Harvard University, Cambridge, MA USA.
⁶ Program in Chemical Biology, Harvard University, Cambridge, MA USA.
⁷ Harvard Stem Cell Institute, Cambridge, MA USA.

Abstract

We compared transcriptomic profiles of cerebral organoids differentiated from induced pluripotent stem cells of eight schizophrenia and eight bipolar disorder patients to identify genes that were differentially expressed in cerebral organoids between two disorders. Gene ontology analysis showed relative up-regulation in schizophrenia organoids of genes related to response to cytokines, antigen binding and clathrin-coated vesicles, while showing up-regulation in bipolar disorder of genes involved in calcium binding. Gene set enrichment analysis revealed enrichment in schizophrenia of genes involved in mitochondrial and oxidative phosphorylation while showing enrichment in bipolar disorder of genes involved in long term potentiation and neuro-transporters. We compared mitochondrial function in cerebral organoids from schizophrenia and bipolar disorder subjects and found that while schizophrenia organoids showed deficits in basal oxygen consumption rate and ATP production when compared to healthy control organoids, while bipolar disorder organoids did not show these deficits. Gene ontology analyses also revealed enrichment in bipolar disorder of genes in ion binding and regulation of transport. Experiments examining the interaction between mitochondria and endoplasmic reticulum in cortical neurons from bipolar disorder subjects showed a significantly lower number of contact sites between mitochondria and endoplasmic reticulum when compared to cortical neurons from schizophrenia patients. These results point to disease-specific deficits in mitochondrial respiration in schizophrenia and in mitochondrial-endoplasmic reticulum interactions in bipolar disorder.

Supplementary information: The online version contains supplementary material available at 10.1007/s44192-023-00031-8.