Synaptic Neurexin Complexes: A Molecular Code for the Logic of Neural Circuits
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Synapses are specialized junctions between neurons in brain that transmit and compute information, thereby connecting neurons into millions of overlapping and interdigitated neural circuits. Here, we posit that the establishment, properties, and dynamics of synapses are governed by a molecular logic that is controlled by diverse trans-synaptic signaling molecules. Neurexins, expressed in thousands of alternatively spliced isoforms, are central components of this dynamic code. Presynaptic neurexins regulate synapse properties via differential binding to multifarious postsynaptic ligands, such as neuroligins, cerebellin/GluD complexes, and latrophilins, thereby shaping the input/output relations of their resident neural circuits. Mutations in genes encoding neurexins and their ligands are associated with diverse neuropsychiatric disorders, especially schizophrenia, autism, and Tourette syndrome. Thus, neurexins nucleate an overall trans-synaptic signaling network that controls synapse properties, which thereby determines the precise responses of synapses to spike patterns in a neuron and circuit and which is vulnerable to impairments in neuropsychiatric disorders.
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This could lead to synaptic loss due to excitotoxicity and reduced synaptogenesis due to the destabilization of nascent synapses, which would result in a net loss of synapses during disease progression.
“This could lead to synaptic loss due to excitotoxicity (6, 33, 34) and reduced synaptogenesis due to the destabilization of nascent synapses (16, 17), which would result in a net loss of synapses during disease progression.”
From Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer’s disease (2020) · cites this paper as [17]
Differential adhesion mediated by neurexins and cerebellins is required for synapse formation and function.
“differential adhesion mediated by neurexins and cerebellins is required for synapse formation and function”
From Single cell transcriptomics reveals spatial and temporal dynamics of gene expression in the developing mouse spinal cord (2019) · cites this paper as Südhof, 2017
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LPHN3 and attention‐deficit/hyperactivity disorder: a susceptibility and pharmacogenetic study
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Dystroglycan Binding to α-Neurexin Competes with Neurexophilin-1 and Neuroligin in the Brain
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LRRTM3 Regulates Excitatory Synapse Development through Alternative Splicing and Neurexin Binding
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The Structure of Neurexin 1α Reveals Features Promoting a Role as Synaptic Organizer
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Structures of C1q-like Proteins Reveal Unique Features among the C1q/TNF Superfamily
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Cerebellins are differentially expressed in selective subsets of neurons throughout the brain
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Molecular Mechanism of MDGA1: Regulation of Neuroligin 2:Neurexin Trans-synaptic Bridges
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Modulation of synaptic function through the α-neurexin–specific ligand neurexophilin-1
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Exon‐disrupting deletions of NRXN1 in idiopathic generalized epilepsy
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Chanda, S., Marro, S. G., Wernig, M., & Südhof, T. C. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1316240110 · Cited by 63 · see citing works
Self-citationThe Cbln family of proteins interact with multiple signaling pathways
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Defining the Ligand Specificity of the Deleted in Colorectal Cancer (DCC) Receptor
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Calsyntenin-3 Molecular Architecture and Interaction with Neurexin 1α
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Neuroligin 2 Is Expressed in Synapses Established by Cholinergic Cells in the Mouse Brain
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The cell biology of synapse formation
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Self-citationAssembly of the presynaptic active zone
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Uncovering the genetic blueprint of the <i>C. elegans</i> nervous system
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Identifying determinants of synaptic specificity by integrating connectomes and transcriptomes
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- Authors
- Südhof, T. C.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Südhof, Thomas C.
- ORCID
- Südhof, Thomas C.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-11
- Volume
- 171
- Issue
- 4
- Pages
- 745-769
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5694349
- OpenAlex
- W2765792294
- Cited by
- 810
- References
- 230
- Citations by year
- 2026: 102 · 2025: 76 · 2024: 92 · 2023: 103 · 2022: 82 · 2021: 109 · 2020: 97 · 2019: 85 · 2018: 61 · 2017: 1
- FWCI
- 8.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIMH (MH052804, MH086403, MH092931)
- NINDS (NS094733)
- NIA (AG04813101)
- HHMI
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- neurexin, trans-synaptic signaling, neuroligins, latrophilin, synaptic plasticity, neural circuits, alternative splicing, neuropsychiatric disorders, schizophrenia, autism spectrum disorder, Tourette syndrome
- MeSH terms
- Animals, Autistic Disorder, Tourette Syndrome, Humans, Membrane Glycoproteins, Neural Pathways, Schizophrenia, Synapses, Signal Transduction, Cell Adhesion Molecules, Neuronal, Alternative Splicing, Protein Isoforms
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