Neurite outgrowth deficits caused by rare PLXNB1 mutation in pediatric bipolar disorder

Abstract

Pediatric Bipolar Disorder (PBD) is a severe mood dysregulation condition experienced by 2 to 3% of children and teens in the United States. It is associated with recurrent episodes of psychosis and depression and an increased risk of suicidality. However, the genetics and neuropathology of PBD are largely unknown. Here, we used a combinatorial family-based approach to characterize the cellular, molecular, genetic, and network-level deficits associated with PBD. We recruited a PBD patient and three unaffected family members from a family with a history of psychiatric illnesses. Using resting-state functional magnetic resonance imaging (rs-fMRI), we detected altered resting-state functional connectivity in the patient as compared to the unaffected sibling. Using transcriptomic profiling of patient and control induced pluripotent stem cell (iPSC) derived telencephalic organoids, we found aberrant signaling in the molecular pathways related to neurite outgrowth. We corroborated the presence of neurite outgrowth deficits in patient iPSC-derived cortical neurons and identified a rare homozygous loss-of-function PLXNB1 variant (c.1360C>C; p.Ser454Arg) in the patient. Expression of wild-typePLXNB1, but not the variant, rescued neurite outgrowth deficit in patient neurons, and expression of the variant caused neurite outgrowth deficit in cortical neurons from PlxnB1knock-out mice.These results indicate that dysregulated PLXNB1signaling may contribute to an increased risk of PBD and other mood dysregulation-related disorders by disrupting neurite outgrowth and functional brain connectivity. Overall, the study established and validated a novel family-based combinatorial approach for studying cellular and molecular deficits in psychiatric disorders.