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Peer-reviewedCC BY-NCNeuron

Neurexin-1γ drives synaptic transmission through structural integration of neurotransmitter release machinery and postsynaptic receptor nanodomains

  • Nirmala Padmanabhan1,2
  • Rebecca E. Twilley1,2
  • Shinichiro Oku1,2,3
  • Mir Sohayeb Rabbi1,2,4,3
  • Adam Skeens5,3
  • Grace Jones5
  • Sandesh Acharya6,7
  • Mohammed Abrar Basha1,2
  • Dinu Rajapakse1,2
  • Cosette Koltek1,2
  • Nabiha Ameena1,2
  • Noushin Ahmadpour1
6 more authors
  • Ying Lao8
  • Jiami Guo6,7
  • Rene P. Zahedi8,9,10
  • Mohiuddin Ahmad11
  • Martin Hruska5
  • Tabrez J. Siddiqui1,2,4,12,13
13 affiliations
  1. 1PrairieNeuro Research Centre, Kleysen Institute for Advanced Medicine, Health Sciences Centre, Winnipeg, MB, R3E 0Z3, Canada
  2. 2Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, R3E 0J9, Canada
  3. 3These authors contributed equally to this work
  4. 4Program in Biomedical Engineering, University of Manitoba
  5. 5Department of Neuroscience, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, West Virginia, USA
  6. 6Department of Cell Biology and Anatomy, Alberta Children’s Hospital Research Institute, University of Calgary
  7. 7Hotchkiss Brain Institute, University of Calgary
  8. 8Manitoba Centre for Proteomics and Systems Biology, University of Manitoba, Winnipeg, MB, R3E 3P4, Canada
  9. 9Department of Internal Medicine, University of Manitoba, Winnipeg, MB, R3A 1R9, Canada.
  10. 10Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, R3E 0J9, Canada.
  11. 11Department of Cell Biology, College of Medicine, University of Oklahoma Health Campus, Oklahoma City, Oklahoma, USA
  12. 12The Children’s Hospital Research Institute of Manitoba, Winnipeg, MB, R3E 3P4, Canada
  13. 13Lead contact
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Abstract

Synaptic transmission requires precise nanoscale alignment of presynaptic release machinery and postsynaptic receptor nanodomains. However, the molecular links bridging these subsynaptic elements remain unresolved. We identify mammalian neurexin-1γ as a presynaptic organizer that directly couples release sites to AMPAR nanodomains. Using complementary mouse lines, an epitope-tagged Nrxn1γ knockin and an Nrxn1γ knockout, and a multimodal approach, we find that neurexin-1γ is enriched at presynaptic release sites precisely opposite AMPAR nanoclusters. Nrxn1γ deletion perturbs synaptic nanoarchitecture, impairs vesicle docking and release, and disrupts transsynaptic nanocolumn alignment and AMPAR positioning, leading to broad deficits in both basal and evoked synaptic transmission, plasticity, and cognitive function. Mechanistically, neurexin-1γ directly binds AMPAR N-termini via its extracellular heparan sulfate glycans, anchoring them with nanoscale precision to neurotransmitter release sites. Our findings establish neurexin-1γ as a nanoscale transsynaptic bridge for optimal synaptic function and circuit activity, revealing an unconventional role for this minimal neurexin variant.

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Cite

BibTeXRIS
BibTeX
@article{padmanabhan2026neurexin1γ,
  title = {{Neurexin-1γ drives synaptic transmission through structural integration of neurotransmitter release machinery and postsynaptic receptor nanodomains}},
  author = {Nirmala Padmanabhan and Rebecca E. Twilley and Shinichiro Oku and Mir Sohayeb Rabbi and Adam Skeens and Grace Jones and Sandesh Acharya and Mohammed Abrar Basha and Dinu Rajapakse and Cosette Koltek and Nabiha Ameena and Noushin Ahmadpour and Ying Lao and Jiami Guo and Rene P. Zahedi and Mohiuddin Ahmad and Martin Hruska and Tabrez J. Siddiqui},
  journal = {Neuron},
  year = {2026},
  month = jul,
  doi = {10.1016/j.neuron.2026.06.018},
  url = {https://doi.org/10.1016/j.neuron.2026.06.018},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - Neurexin-1γ drives synaptic transmission through structural integration of neurotransmitter release machinery and postsynaptic receptor nanodomains
AU  - Nirmala Padmanabhan
AU  - Rebecca E. Twilley
AU  - Shinichiro Oku
AU  - Mir Sohayeb Rabbi
AU  - Adam Skeens
AU  - Grace Jones
AU  - Sandesh Acharya
AU  - Mohammed Abrar Basha
AU  - Dinu Rajapakse
AU  - Cosette Koltek
AU  - Nabiha Ameena
AU  - Noushin Ahmadpour
AU  - Ying Lao
AU  - Jiami Guo
AU  - Rene P. Zahedi
AU  - Mohiuddin Ahmad
AU  - Martin Hruska
AU  - Tabrez J. Siddiqui
PY  - 2026
DA  - 2026/07/21
JO  - Neuron
DO  - 10.1016/j.neuron.2026.06.018
UR  - https://doi.org/10.1016/j.neuron.2026.06.018
AB  - Synaptic transmission requires precise nanoscale alignment of presynaptic release machinery and postsynaptic receptor nanodomains. However, the molecular links bridging these subsynaptic elements remain unresolved. We identify mammalian neurexin-1γ as a presynaptic organizer that directly couples release sites to AMPAR nanodomains. Using complementary mouse lines, an epitope-tagged Nrxn1γ knockin and an Nrxn1γ knockout, and a multimodal approach, we find that neurexin-1γ is enriched at presynaptic release sites precisely opposite AMPAR nanoclusters. Nrxn1γ deletion perturbs synaptic nanoarchitecture, impairs vesicle docking and release, and disrupts transsynaptic nanocolumn alignment and AMPAR positioning, leading to broad deficits in both basal and evoked synaptic transmission, plasticity, and cognitive function. Mechanistically, neurexin-1γ directly binds AMPAR N-termini via its extracellular heparan sulfate glycans, anchoring them with nanoscale precision to neurotransmitter release sites. Our findings establish neurexin-1γ as a nanoscale transsynaptic bridge for optimal synaptic function and circuit activity, revealing an unconventional role for this minimal neurexin variant.
SN  - 0896-6273
SN  - 1097-4199
ER  -