Cross-platform validation of neurotransmitter release impairments in schizophrenia patient-derived NRXN1 -mutant neurons
| العنوان: | Cross-platform validation of neurotransmitter release impairments in schizophrenia patient-derived NRXN1 -mutant neurons |
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| المؤلفون: | Philip Dexheimer, Jeffrey L. Dage, Xianglong Zhang, Thomas J. Ward, Yu-Wen Alvin Huang, Yingfei Liu, Marius Wernig, Zhiping P. Pang, Tamas Danko, ChangHui Pak, Jinzhao Wang, Vincent R. Mirabella, Kang Jin, Michael McLachlan, Madhuri Vangipuram, Carolin Purmann, Jennifer C. Moore, Junyi Ma, Bradley J. Swanson, Sarah Grieder, Eric E. Bardes, Douglas F. Levinson, Alexis Mitelpunkt, Bruce J. Aronow, Alexander E. Urban, Thomas C. Südhof, Pingping Qu |
| المصدر: | Proc Natl Acad Sci U S A |
| بيانات النشر: | Proceedings of the National Academy of Sciences, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Heterozygote, Mutant, Induced Pluripotent Stem Cells, Neurexin, Gene Expression, Neuroligin, Neurotransmission, Biology, medicine.disease_cause, Cohort Studies, Synapse, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, medicine, Humans, CASK, Induced pluripotent stem cell, Neurotransmitter, Neural Cell Adhesion Molecules, Cells, Cultured, Embryonic Stem Cells, Neurons, Mutation, Neurotransmitter Agents, Multidisciplinary, Drug discovery, Calcium-Binding Proteins, Biological Sciences, Phenotype, Embryonic stem cell, 030104 developmental biology, chemistry, Case-Control Studies, Cell Transdifferentiation, Schizophrenia, NMDA receptor, Guanylate Kinases, Neuroscience, 030217 neurology & neurosurgery |
| الوصف: | Heterozygous NRXN1 deletions constitute the most prevalent currently known single-gene mutation predisposing to schizophrenia. Previous studies showed that engineered heterozygous NRXN1 deletions impaired neurotransmitter release in human neurons, suggesting a synaptic pathophysiological mechanism. Utilizing this observation for drug discovery, however, requires confidence in its robustness and validity. Here, we describe a multi-center effort to test the generality of this pivotal observation, using independent analyses at two laboratories of patient-derived and newly engineered human neurons with heterozygous NRXN1 deletions. We show that in neurons that were trans-differentiated from induced pluripotent stem cells derived from three NRXN1-deletion patients, the same impairment in neurotransmitter release was observed as in engineered NRXN1-deficient neurons. This impairment manifested as a decrease in spontaneous synaptic events and in evoked synaptic responses, and an alteration in synaptic paired-pulse depression. Nrxn1-deficient mouse neurons generated from embryonic stem cells by the same method as human neurons did not exhibit impaired neurotransmitter release, suggesting a human-specific phenotype. NRXN1 deletions produced a reproducible increase in the levels of CASK, an intracellular NRXN1-binding protein, and were associated with characteristic gene expression changes. Thus, heterozygous NRXN1 deletions robustly impair synaptic function in human neurons regardless of genetic background, enabling future drug discovery efforts. |
| تدمد: | 1091-6490 0027-8424 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4862173dfbc4ea72fe8169d61db3d2ea https://doi.org/10.1073/pnas.2025598118 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....4862173dfbc4ea72fe8169d61db3d2ea |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 00278424 |
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