Modeling a Neurexin-3α Human Mutation in Mouse Neurons Identifies a Novel Role in the Regulation of Transsynaptic Signaling and Neurotransmitter Release at Excitatory Synapses
| العنوان: | Modeling a Neurexin-3α Human Mutation in Mouse Neurons Identifies a Novel Role in the Regulation of Transsynaptic Signaling and Neurotransmitter Release at Excitatory Synapses |
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| المؤلفون: | Susana Restrepo, Jason Aoto, Nora J. Langer, Kylan A. Nelson |
| المصدر: | J Neurosci |
| بيانات النشر: | Society for Neuroscience, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Primary Cell Culture, Mutation, Missense, Neurexin, Nerve Tissue Proteins, Biology, Neurotransmission, Hippocampus, Synaptic Transmission, Synapse, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Postsynaptic potential, Intellectual Disability, Animals, Humans, Missense mutation, Neurotransmitter, Research Articles, Neurons, Epilepsy, integumentary system, General Neuroscience, fungi, Excitatory Postsynaptic Potentials, Long-term potentiation, Mice, Inbred C57BL, Protein Transport, HEK293 Cells, 030104 developmental biology, chemistry, Gene Knockdown Techniques, Excitatory postsynaptic potential, Female, Synaptic Vesicles, Neuroscience, 030217 neurology & neurosurgery |
| الوصف: | Presynaptic α-neurexins are highly expressed and more frequently linked to neuropsychiatric and neurodevelopmental disorders than β-neurexins. However, how extracellular sequences specific to α-neurexins enable synaptic transmission is poorly understood. We identified a mutation in an extracellular region of neurexin-3α (A687T), located in a region conserved among α-neurexins and throughout vertebrate evolution, in a patient diagnosed with profound intellectual disability and epilepsy. We systematically interrogated this mutation using a knockdown-replacement approach, and discovered that the A687T mutation enhanced presynaptic morphology and increased two critical presynaptic parameters: (1) presynaptic release probability, and (2) the size of the readily releasable pool exclusively at excitatory synapses in mixed sex primary mouse hippocampal cultures. Introduction of the mutationin vivoand subsequent analysis inex vivobrain slices made from male and female mice revealed a significant increase in excitatory presynaptic neurotransmission that occluded presynaptic but not postsynaptic LTP. Mechanistically, neurexin-3αA687Tenhanced binding to LRRTM2 without altering binding to postsynaptic neuroligin-1. Thus, neurexin-3αA687Tunexpectedly produced the first neurexin presynaptic gain-of-function phenotype and revealed unanticipated novel insights into how α-neurexin extracellular sequences govern both transsynaptic adhesion and presynaptic neurotransmitter release.SIGNIFICANCE STATEMENTDespite decades of scientific scrutiny, how precise α-neurexin extracellular sequences control synapse function remains enigmatic. One largely unpursued avenue to identify the role of precise extracellular sequences is the interrogation of naturally occurring missense mutations. Here, we identified a neurexin-3α missense mutation in a compound heterozygous patient diagnosed with profound intellectual disability and epilepsy and systematically interrogated this mutation. Usingin vitroandin vivomolecular replacement, electrophysiology, electron microscopy, and structure–function analyses, we reveal a novel role for neurexin-3α, unanticipated based on α-neurexin knock-out models, in controlling presynaptic morphology and neurotransmitter release at excitatory synapses. Our findings represent the first neurexin gain-of-function phenotype and provide new fundamentally important insight into the synaptic biology of α-neurexins. |
| تدمد: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.1261-19.2019 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f9863ee12ceff3f1f608a903147ad716 https://doi.org/10.1523/jneurosci.1261-19.2019 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....f9863ee12ceff3f1f608a903147ad716 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15292401 02706474 |
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| DOI: | 10.1523/jneurosci.1261-19.2019 |