Abnormalities in migration of neural precursor cells in familial bipolar disorder

Abstract

Cellular migration is a ubiquitous feature of development that brings brain cells into appropriate spatial relationships. Cortical thinning has been reported in post-mortem brain samples of patients with bipolar disorder (BD). It could be that defective cellular migration during brain development is one of the contributing mechanisms in BD pathogenesis, leading to abnormalities reported at post-mortem, and during brain imaging. To probe the role of cellular migration in BD, we conducted time-lapse analysis of migration of neural precursor cells (NPCs) previously generated in our laboratory. Two NPC lines (B1 and B2) and one control line (C1) were used for the cell migration experiments. Time-lapse images were recorded every 15 min, for 15 hours, and analysed for speed and direction of cellular migration. Abnormalities in cellular migration was a common feature observed in both patient-derived NPCs. Consequently, we investigated underlying mechanistic irregularities in B1 and B2 lines that may contribute to the observed phenotype. To this end, transcriptional changes were compared between the patient-derived cells with the control line. Additionally, we examined exonic variations in genes related to cellular migration or motility. Our analysis showed downregulation of multiple genes that are all part of the EGF/ERBB signaling pathway. Collective dysregulation may be producing the defective cellular phenotype. These cellular migration abnormalities may be linked to structural changes in the brain reported in bipolar disorder.