Is it possible to mimic mental disorders in a laboratory dish?

Schizophrenia and bipolar disorder are severe mental disorders affecting mainly thoughts and mood, respectively. During the last decades the identification of pathological mechanisms underlying mental disorders has relied on rodent and cancer cell lineage models, along with post-mortem brain specimens. However, post-mortem brain tissue present conservation issues, and interference of drug treatment and advanced age at the moment of death. In addition, rodent brain cells lack the complexity that human brain cells gained along evolution, and cell lineages are derived from tumours, thus presenting confounding characteristics of cancer cells.

An attractive alternative to these models is artificially converting skin cells from patients into a type of cells called induced pluripotent stem cells (iPS cells). The iPS cells can be “banked” in liquid nitrogen tanks for long periods of time. Because iPS cells are pluripotent, they can be differentiated into any cells present in the human body, including brain cells, such as neurons and astrocytes. Another possibility is a direct conversion of iPS cells into the so-called brain organoids, which are three-dimensional cell aggregates containing all brain cell types, such as neural stem cells, neuron, astrocytes, oligodendrocytes and microglia. iPS cell models are ideal to study disorders influenced by genetic factors, such as schizophrenia and bipolar disorder, since the resulting differentiated brain cells retain the genetic background of the cell donors [1].

Looking for EEG-like signals in cerebral organoids

The brain of individuals with schizophrenia and bipolar disorder present unbalanced neurotransmission between excitatory and inhibitory neurotransmitters, which result in alterations in electrical signals in the brain. By placing electrodes on someone`s skull, it is possible to detect and record these electrical signals through a test called electroencephalogram (EEG). When compared to the signals from healthy individuals, patients with schizophrenia and bipolar disorder present alterations that can be used to help in the identification of these disorders (diagnosis) and for evaluating the efficacy of drug treatments (treatment follow-up).

Recently, it has been reported that the conversion of iPSCs into three-dimensional structures resembling the brain cortex development (brain organoids called cortical spheroids) results in EEG-like signals similar to the brain of preterm babies [2]. This discovery inspired us to convert iPSCs from patients with schizophrenia and bipolar disorder into cortical spheroids to test the electrical signals generated by these structures in the laboratory setup. Our hypothesis is that the electrical signals produced by the cortical spheroids in the laboratory may match with the EEG from the cell donors.

In order to test this hypothesis, we wait for the cortical spheroids derived from iPSCs to reach maturity (after 8 months of growth in a laboratory dish), and then we measure electrical signals that are like a laboratory version of the EEG recorded in the patients. If successful, the signals from the cortical spheroids in the laboratory will match with the EEG of the donor patients. In this case, we will be able to use cortical spheroids to understand molecular mechanisms provoking EEG alterations in mental disorders and to predict the effects of drugs on the EEG signals in patients by “treating” their corresponding cortical spheroids with different medicines.

Besides studying electric signals, this is an interdisciplinary project, involving electrophysiologists (experts in electrical signals), immunologists, geneticists, biochemists, and mathematicians (see figure below).

References

1. Reis de Assis, D. et al. Using iPSC Models to Understand the Role of Estrogen in Neuron-Glia Interactions in Schizophrenia and Bipolar Disorder. Cells 10, doi:10.3390/cells10020209 (2021). 

2. Trujillo, C. A. et al. Complex Oscillatory Waves Emerging from Cortical Organoids Model Early Human Brain Network Development. Cell Stem Cell 25, 558-569.e557, doi:10.1016/j.stem.2019.08.002 (2019).