Abnormalities in the migration of neural precursor cells in familial bipolar disorder

Abstract

Cellular migration is a ubiquitous feature that brings brain cells into appropriate spatial relationships over time; and it helps in the formation of a functional brain. We studied the migration patterns of induced pluripotent stem cell-derived neural precursor cells (NPCs) from individuals with familial bipolar disorder (BD) in comparison with healthy controls. The BD patients also had morphological brain abnormalities evident on magnetic resonance imaging. Time-lapse analysis of migrating cells was performed, through which we were able to identify several parameters that were abnormal in cellular migration, including the speed and directionality of NPCs. We also performed transcriptomic analysis to probe the mechanisms behind the aberrant cellular phenotype identified. Our analysis showed the downregulation of a network of genes, centering on EGF/ERBB proteins. The present findings indicate that collective, systemic dysregulation may produce the aberrant cellular phenotype, which could contribute to the functional and structural changes in the brain reported for bipolar disorder.

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Peer review report

Title: Abnormalities in migration of neural precursor cells in familial bipolar disorder

version: 6

Referee: Shani Stern

Institution: University of Haifa

email: sstern@univ.haifa.ac.il

ORCID iD: 0000-0002-2644-7068

General assessment

I have read the study by Sukumaran et al. The authors describe that NPCs derived from bipolar disorder patients using induced pluripotent stem cells show abnormal migration and that transcriptionally there is a dysregulation of a network of genes that relate to on EGF/ERBB proteins. Overall, the study is interesting. However, some points should be addressed. See below.

The following points are important to take into consideration:

Some English edits are required. Also, some acronyms appear before their definition (for example MSD).
In the introduction, some important studies that describe transcriptomics of BD patients should be described such as Santos et al 2021 and also neuronal phenotypes such as hyperexcitability and physiological instabilities.
The transcriptomics is performed only for one of the control lines although there are 3 controls. More control samples should be taken for the gene expression analysis.
The figures are not in the correct order.
The damaging variants of the patients are not described. Although there are references to previous publications, since this may be central it is good to add a table describing these variants in the patients and in the controls.
The differentiation to which type of neurons should be briefly described (although there is a reference to previous publications, but this should be mentioned).
The statistical analysis is not very clear. Moreover, the images of the migration assays are not convincing enough that indeed there is a significant difference. How many times was this performed? This should be repeated with several cultures, especially since the number of patients and controls is small. It would be more convincing if this is reproducible over several repetitions.
It would be good to also include representative videos in the supplementary.

Decision

Requires revisions: The manuscript contains objective errors or fundamental flaws that must be addressed and/or major revisions are suggested.

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Abnormalities in the migration of neural precursor cells in familial bipolar disorder

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