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

Molecular Psychiatry volume 28, pages 2525–2539 (2023)Cite this article

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Abstract

Pediatric bipolar disorder (PBD) is a severe mood dysregulation condition that affects 0.5–1% of children and teens in the United States. It is associated with recurrent episodes of mania 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 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 an 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) responsible for the deficits in the patient. Expression of wild-type PLXNB1, but not the variant, rescued neurite outgrowth in patient neurons, and expression of the variant caused the neurite outgrowth deficits in cortical neurons from PlxnB1 knockout mice. These results indicate that dysregulated PLXNB1 signaling may contribute to an increased risk of PBD and other mood dysregulation-related disorders by disrupting neurite outgrowth and functional brain connectivity. Overall, this study established and validated a novel family-based combinatorial approach for studying cellular and molecular deficits in psychiatric disorders and identified dysfunctional PLXNB1 signaling and neurite outgrowth as potential risk factors for PBD.

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Fig. 1: Functional brain connectivity differences in an individual with PBD.
Fig. 2: Dysregulated gene expression in GO pathways related to neurite outgrowth in patient iPSC-derived organoids.
Fig. 3: Impaired neurite outgrowth in patient iPSC-derived cortical neurons.
Fig. 4: Homozygous loss-of-function mutation in PLXNB1 identified in PBD patient.
Fig. 5: Homozygous PLXNB1 Ser454Arg mutation causes neurite outgrowth deficits.

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Acknowledgements

The authors are thankful to the family that participated in our study; to Jubel Morgan for collection of biological samples and Dr. Roland Friedel and Suzanne Paradis for sharing PLXNB1-null mice; to Dr. Kandy Napan for help with breeding and establishing mouse colony; to Dr. Xuewu Zhang for sharing PlexinB1 plasmid; to Drs. Megan Williams, Sungjin Park, Richard Dorsky, and Jan Christian for advice on experiments and comments on the manuscript; to Dr. Brian Dalley, Opal Allen, and Brian Lohman and the Utah high-throughput genomics facility for help with sequencing and data analysis; to the Utah cell imaging facility for help with imaging; to Dr. Elliott Farris for help with analysis of variant data; and to Dr. Marvin B. Moore and the Center for High Performance Computing for help with processing and analysis of whole-exome sequencing data. The authors would also like to thank the funding sources that made this study possible: the Utah Neuroscience Initiative, the Utah Genome Project, and the NIH Developmental Biology Training Grant (Award Number: T32HD007491).

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Author notes

  1. Melissa Lopez-Larson

    Present address: Lopez-Larson and Associates, Park City, UT, USA

Authors and Affiliations

  1. Department of Neurobiology, University of Utah, Salt Lake City, UT, USA

    Guang Yang, H. M. Arif Ullah, Mark Libowitz & Alex Shcheglovitov

  2. Neuroscience Graduate Program, University of Utah, Salt Lake City, UT, USA

    Guang Yang & Alex Shcheglovitov

  3. Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, USA

    Ethan Parker & Alex Shcheglovitov

  4. Department of Human Genetics, University of Utah, Salt Lake City, UT, USA

    Bushra Gorsi & Mark Yandell

  5. Utah Center for Genetic Discovery, Salt Lake City, UT, USA

    Bushra Gorsi

  6. Clinical & Translational Research Core, Utah Clinical & Translational Research Institute, Salt Lake City, UT, USA

    Colin Maguire & Alex Shcheglovitov

  7. Department of Radiology, University of Utah, Salt Lake City, UT, USA

    Jace B. King & Jeffrey S. Anderson

  8. Department of Psychiatry, University of Utah, Salt Lake City, UT, USA

    Hilary Coon, Melissa Lopez-Larson & Alex Shcheglovitov

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Contributions

MLL, JBK—recruitment and evaluations of human subjects; GY, HMAU, EP JBK, JY, CM—data acquisition, analyses, and interpretation; BG, ML, HC, MY—data analysis and interpretation; MLL, JSA, MY, AS—conceived the idea and supervised the study; GY, AS—wrote the manuscript; all authors commented on the manuscript.

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Correspondence to Alex Shcheglovitov.

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Yang, G., Ullah, H.M.A., Parker, E. et al. Neurite outgrowth deficits caused by rare PLXNB1 mutation in pediatric bipolar disorder. Mol Psychiatry 28, 2525–2539 (2023). https://doi.org/10.1038/s41380-023-02035-w

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  • DOI: https://doi.org/10.1038/s41380-023-02035-w

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