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Stem Cell "Mini-Brains" Useful for Studying the Biology of Bipolar Disorder

Key findings

  • In this study, induced pluripotent stem cells (iPSCs) were generated from skin cells from patients with bipolar disorder (BPD) and healthy control subjects, which were then used to create cerebral organoids—three-dimensional neuronal culture systems that recapitulate the development of the human forebrain
  • The gene expression pattern in BPD organoids was distinctly different from that in control organoids, with 4,473 genes that were differentially expressed between the BPD and control cerebral organoids
  • When compared with control cerebral organoids, BPD organoids showed downregulation of genes involved in cell adhesion, neurodevelopment and synaptic biology and upregulation of genes involved in immune signaling
  • In experiments using multi-electrode arrays to interrogate neuronal firing patterns, BPD and control cerebral organoids exhibited similar electrical activity at baseline, but BPD organoids showed diminished response to electrical stimulation and to depolarization

A major obstacle to investigating psychiatric disorders has been the infeasibility of accessing live human brain tissue for laboratory experiments. In recent years, though, scientists have discovered new methods to reprogram easily accessible skin cells into pluripotent stem cells, which can then be used to generate a range of neuronal cell types and tissue with disease-specific genetic backgrounds.

Furthermore, induced pluripotent stem cells (iPSCs) can be used to generate cerebral organoids in the laboratory. These brain organoids are three-dimensional ex vivo culture systems that recapitulate human cortical development and contain many of the neuronal and glial cell subtypes found in the human brain. These brain organoids enable careful examination and dissection of networks of connectivity between the neuronal cells.

In Genome Medicine, Rakesh Karmacharya, MD, PhD, director of Stem Cell Research at the Center for Experimental Drugs & Diagnostics at Massachusetts General Hospital and associate professor in the Center for Genomic Medicine, Annie Kathuria, PhD, postdoctoral fellow in his laboratory, and colleagues have published the first report of success in using cerebral organoids to study the biology of bipolar disorder (BPD).

Study Details

Through skin biopsies, the researchers collected fibroblasts from eight patients with BPD and eight sex- and age-matched healthy individuals who did not have a family history of BPD or schizophrenia.

The fibroblasts were reprogrammed into iPSCs, which were differentiated to generate cerebral organoids patterned after the human dorsal forebrain.

Differences in Gene Expression Profiles

The gene expression pattern in BPD organoids was distinctly different from that in control organoids, for both coding and noncoding genes. 4,473 genes were differentially expressed between the BPD and control cerebral organoids.

Neurodevelopmental Roots of BPD

In BPD organoids, compared with control organoids, there was:

  • Downregulation of genes involved in cell adhesion, neurodevelopment and synaptic biology
  • Upregulation of genes involved in immune signaling

A network analysis of differentially expressed genes determined the central hub gene was neurocan (NCAN), which was significantly downregulated in BPD cerebral organoids. Independently, genome-wide association studies (GWAS) have implicated variations in NCAN as a risk factor for BPD.

The NCAN protein is involved in cell adhesion and neuronal migration, processes that are pivotal during neurodevelopment.

Deficits in Neurotransmission

Control cerebral organoids exhibited a significant increase in spike frequency in response to an electrical stimulus, but BPI organoids showed no such increase. The same was true for spike frequency in response to neuronal depolarization with potassium chloride.

A New Direction for Research

BPD has a strong genetic component, with heritability estimated at more than 70%. However, in studies of patients with neuroimaging and experiments with primary cells or postmortem tissue, it is difficult to separate the effects of genetic factors from those of drugs, stress, the patient's environment or the disease process itself. Ex vivo studies using patient stem cells enable studies examining the specific contribution of the complex genetic background.

Three-dimensional cellular models generated from patient-derived iPSCs should be valuable for studying not only BPD but also other neuropsychiatric disorders and will lay the foundation for the disease biology that can help identify molecular targets for novel therapeutics.

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