Conditional Deletion of All Neurexins Defines Diversity of Essential Synaptic Organizer Functions for Neurexins
- 1Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University Medical School, 265 Campus Drive, Stanford, CA 94305, U
Abstract
Presynaptic neurexins are key regulators of synapse properties that arguably represent the best-studied synaptic adhesion molecules. Despite thousands of papers, however, no direct comparison of overall neurexin functions in different types of synapses is available. A decade ago, we provided such an analysis but we recently retracted this paper because four images contained microduplications that, although without discernible impact on the paper's conclusions, could not be corrected. As a result, the scientific community lost access to primary data that established the fundamental principle that neurexins perform profoundly different functions in different types of synapses. In the present study, we have therefore reanalyzed the original raw data and expanded their conclusions with new experiments to document, in a single study, the basic contributions of neurexins to different synapses. We used triple conditional knockout mice targeting all neurexins except for Neurexin-1r and applied neuron-specific manipulations combined with slice electrophysiology, two-photon Ca2+-imaging, and immunohistochemistry. With this approach, we focused on excitatory climbing-fiber synapses in the cerebellum and on inhibitory synapses formed by parvalbumin- or somatostatin-positive neurons in the cerebellum, hippocampus, and medial prefrontal cortex. Our results show that pan-neurexin deletions produce dramatically different phenotypes in synapses, ranging from modest to massive impairments in synapse assembly (climbing-fiber and parvalbumin-positive synapses) to severe but selective decreases in action potential-induced presynaptic Ca2+-transients (somatostatin-positive synapses). Thus, neurexins perform powerful but distinct context-dependent roles in different synapses that shape the brain's circuits.
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BibTeX
@misc{jiang2026conditional,
title = {{Conditional Deletion of All Neurexins Defines Diversity of Essential Synaptic Organizer Functions for Neurexins}},
author = {M. Jiang and Y. Li and M. Artyukhova and L. Zhang and S. Luo and W. Zhan and B. Zhang and O. Gokce and T. C. Sudhof},
howpublished = {bioRxiv},
year = {2026},
month = jul,
doi = {10.64898/2026.07.15.738748},
url = {https://www.biorxiv.org/content/10.64898/2026.07.15.738748v2},
note = {CC BY},
}
RIS
TY - UNPB
TI - Conditional Deletion of All Neurexins Defines Diversity of Essential Synaptic Organizer Functions for Neurexins
AU - M. Jiang
AU - Y. Li
AU - M. Artyukhova
AU - L. Zhang
AU - S. Luo
AU - W. Zhan
AU - B. Zhang
AU - O. Gokce
AU - T. C. Sudhof
PY - 2026
DA - 2026/07/15
PB - bioRxiv
DO - 10.64898/2026.07.15.738748
UR - https://www.biorxiv.org/content/10.64898/2026.07.15.738748v2
AB - Presynaptic neurexins are key regulators of synapse properties that arguably represent the best-studied synaptic adhesion molecules. Despite thousands of papers, however, no direct comparison of overall neurexin functions in different types of synapses is available. A decade ago, we provided such an analysis but we recently retracted this paper because four images contained microduplications that, although without discernible impact on the paper's conclusions, could not be corrected. As a result, the scientific community lost access to primary data that established the fundamental principle that neurexins perform profoundly different functions in different types of synapses. In the present study, we have therefore reanalyzed the original raw data and expanded their conclusions with new experiments to document, in a single study, the basic contributions of neurexins to different synapses. We used triple conditional knockout mice targeting all neurexins except for Neurexin-1r and applied neuron-specific manipulations combined with slice electrophysiology, two-photon Ca2+-imaging, and immunohistochemistry. With this approach, we focused on excitatory climbing-fiber synapses in the cerebellum and on inhibitory synapses formed by parvalbumin- or somatostatin-positive neurons in the cerebellum, hippocampus, and medial prefrontal cortex. Our results show that pan-neurexin deletions produce dramatically different phenotypes in synapses, ranging from modest to massive impairments in synapse assembly (climbing-fiber and parvalbumin-positive synapses) to severe but selective decreases in action potential-induced presynaptic Ca2+-transients (somatostatin-positive synapses). Thus, neurexins perform powerful but distinct context-dependent roles in different synapses that shape the brain's circuits.
ER -