Calsyntenin-3, an atypical cadherin, suppresses inhibitory synapses but increases excitatory parallel-fiber synapses in cerebellum
- Howard Hughes Medical Institute, Stanford University, United States
- Huazhong University of Science and Technology, China
- Stanford University, United States
- Daegu Gyeongbuk Institute of Science and Technology, Republic of Korea
Abstract
Cadherins contribute to the organization of nearly all tissues, but the functions of several evolutionarily conserved cadherins, including those of calsyntenins, remain enigmatic. Puzzlingly, two distinct, non-overlapping functions for calsyntenins were proposed: As postsynaptic neurexin ligands in synapse formation, or as presynaptic kinesin adaptors in vesicular transport. Here, we show that, surprisingly, acute CRISPR-mediated deletion of calsyntenin-3 in mouse cerebellum in vivo causes a large decrease in inhibitory synapse, but a robust increase in excitatory parallel-fiber synapses in Purkinje cells. As a result, inhibitory synaptic transmission was suppressed, whereas parallel-fiber synaptic transmission was enhanced in Purkinje cells by the calsyntenin-3 deletion. No changes in the dendritic architecture of Purkinje cells or in climbing-fiber synapses were detected. Sparse selective deletion of calsyntenin-3 only in Purkinje cells recapitulated the synaptic phenotype, indicating that calsyntenin-3 acts by a cell-autonomous postsynaptic mechanism in cerebellum. Thus, by promoting formation of excitatory parallel-fiber synapses and decreasing formation of inhibitory synapses in the same neuron, calsyntenin-3 functions as a postsynaptic adhesion molecule that regulates the excitatory/inhibitory balance in Purkinje cells.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting files. All numerical data have been provided in a zipped folder.
Article and author information
Author details
Funding
National Institute of Mental Health (MH052804)
- Thomas C Südhof
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Gary L Westbrook, Oregon Health and Science University, United States
Ethics
Animal experimentation: All animal experiments: All protocols were carried out under the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals and were approved by the Administrative Panel on Laboratory Animal Care (APLAC) at Stanford University and institutional animal care and use committee (IACUC). The animal protocol #20787 was approved by Stanford University APLAC and IACUC. All surgeries were performed under avertin anesthesia and carprofen analgesia, and every effort was made to minimize suffering, pain, and distress.
Version history
- Received: May 25, 2021
- Preprint posted: May 31, 2021 (view preprint)
- Accepted: April 14, 2022
- Accepted Manuscript published: April 14, 2022 (version 1)
- Accepted Manuscript updated: April 21, 2022 (version 2)
- Version of Record published: May 3, 2022 (version 3)
Copyright
© 2022, Liu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Calsyntenin-3, an atypical cadherin, suppresses inhibitory synapses but increases excitatory parallel-fiber synapses in cerebellum
eLife 11:e70664.
https://doi.org/10.7554/eLife.70664
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