Calsyntenin-3 interacts with both a- And b-neurexins in the regulation of excitatory synaptic innervation in specific Schaffer collateral pathways

Hyeonho Kim; Dongwook Kim; Jinhu Kim; Hee Yoon Lee; Dongseok Park; Hyeyeon Kang; Keiko Matsuda; Fredrik H. Sterky; Michisuke Yuzaki; Jin Young Kim; Se Young Choi; Jaewon Ko; Ji Won Um

doi:10.1074/jbc.ra120.013077

Calsyntenin-3 interacts with both a- And b-neurexins in the regulation of excitatory synaptic innervation in specific Schaffer collateral pathways

Hyeonho Kim, Dongwook Kim, Jinhu Kim, Hee Yoon Lee, Dongseok Park, Hyeyeon Kang, Keiko Matsuda, Fredrik H. Sterky, Michisuke Yuzaki, Jin Young Kim, Se Young Choi, Jaewon Ko, Ji Won Um

Department of Brain Sciences

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

Abstract

Calsyntenin-3 (Clstn3) is a postsynaptic adhesion molecule that induces presynaptic differentiation via presynaptic neurexins (Nrxns), but whether Nrxns directly bind to Clstn3 has been a matter of debate. Here, using LC-MS/MS-based protein analysis, confocal microscopy, RNAscope assays, and electrophysiological recordings, we show that b-Nrxns directly interact via their LNS domain with Clstn3 and Clstn3 cadherin domains. Expression of splice site 4 (SS4) insert-positive b-Nrxn variants, but not insert-negative variants, reversed the impaired Clstn3 synaptogenic activity observed in Nrxn-deficient neurons. Consistently, Clstn3 selectively formed complexes with SS4-positive Nrxns in vivo. Neuron-specific Clstn3 deletion caused significant reductions in number of excitatory synaptic inputs. Moreover, expression of Clstn3 cadherin domains in CA1 neurons of Clstn3 conditional knockout mice rescued structural deficits in excitatory synapses, especially within the stratum radiatum layer. Collectively, our results suggest that Clstn3 links to SS4-positive Nrxns to induce presynaptic differentiation and orchestrate excitatory synapse development in specific hippocampal neural circuits, including Schaffer collateral afferents.

Original language	English
Pages (from-to)	9244-9262
Number of pages	19
Journal	Journal of Biological Chemistry
Volume	295
Issue number	27
DOIs	https://doi.org/10.1074/jbc.ra120.013077
State	Published - 3 Jul 2020

Bibliographical note

Publisher Copyright:
© 2020 Kim et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc. deletion of Clstn3 in neurons led to drastic reductions in excitatory synapse structures. Finally, adeno-associated virus-mediated expression of Nrxn-binding CST-3 cadherin domains was sufficient to rescue decreased excitatory synapse puncta density in CA1 stratum radiatum layers of Clstn3-deficient mice. Viewed together, our results revise our previous molecular model, showing that Clstn3 directly interacts with SS4-positive Nrxn splice variants to induce presynaptic differentiation, and suggesting synapse-organizing functions of Clstn3 that may control specific synaptic inputs from Schaffer-collateral afferents in the hippocampus.

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10.1074/jbc.ra120.013077

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Kim, H., Kim, D., Kim, J., Lee, H. Y., Park, D., Kang, H., Matsuda, K., Sterky, F. H., Yuzaki, M., Kim, J. Y., Choi, S. Y., Ko, J., & Um, J. W. (2020). Calsyntenin-3 interacts with both a- And b-neurexins in the regulation of excitatory synaptic innervation in specific Schaffer collateral pathways. Journal of Biological Chemistry, 295(27), 9244-9262. https://doi.org/10.1074/jbc.ra120.013077

@article{d6562ad932cf4a8481b3569c4c420d8f,

title = "Calsyntenin-3 interacts with both a- And b-neurexins in the regulation of excitatory synaptic innervation in specific Schaffer collateral pathways",

abstract = "Calsyntenin-3 (Clstn3) is a postsynaptic adhesion molecule that induces presynaptic differentiation via presynaptic neurexins (Nrxns), but whether Nrxns directly bind to Clstn3 has been a matter of debate. Here, using LC-MS/MS-based protein analysis, confocal microscopy, RNAscope assays, and electrophysiological recordings, we show that b-Nrxns directly interact via their LNS domain with Clstn3 and Clstn3 cadherin domains. Expression of splice site 4 (SS4) insert-positive b-Nrxn variants, but not insert-negative variants, reversed the impaired Clstn3 synaptogenic activity observed in Nrxn-deficient neurons. Consistently, Clstn3 selectively formed complexes with SS4-positive Nrxns in vivo. Neuron-specific Clstn3 deletion caused significant reductions in number of excitatory synaptic inputs. Moreover, expression of Clstn3 cadherin domains in CA1 neurons of Clstn3 conditional knockout mice rescued structural deficits in excitatory synapses, especially within the stratum radiatum layer. Collectively, our results suggest that Clstn3 links to SS4-positive Nrxns to induce presynaptic differentiation and orchestrate excitatory synapse development in specific hippocampal neural circuits, including Schaffer collateral afferents.",

author = "Hyeonho Kim and Dongwook Kim and Jinhu Kim and Lee, {Hee Yoon} and Dongseok Park and Hyeyeon Kang and Keiko Matsuda and Sterky, {Fredrik H.} and Michisuke Yuzaki and Kim, {Jin Young} and Choi, {Se Young} and Jaewon Ko and Um, {Ji Won}",

note = "Publisher Copyright: {\textcopyright} 2020 Kim et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc. deletion of Clstn3 in neurons led to drastic reductions in excitatory synapse structures. Finally, adeno-associated virus-mediated expression of Nrxn-binding CST-3 cadherin domains was sufficient to rescue decreased excitatory synapse puncta density in CA1 stratum radiatum layers of Clstn3-deficient mice. Viewed together, our results revise our previous molecular model, showing that Clstn3 directly interacts with SS4-positive Nrxn splice variants to induce presynaptic differentiation, and suggesting synapse-organizing functions of Clstn3 that may control specific synaptic inputs from Schaffer-collateral afferents in the hippocampus.",

year = "2020",

month = jul,

day = "3",

doi = "10.1074/jbc.ra120.013077",

language = "English",

volume = "295",

pages = "9244--9262",

journal = "Journal of Biological Chemistry",

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Kim, H, Kim, D, Kim, J, Lee, HY, Park, D, Kang, H, Matsuda, K, Sterky, FH, Yuzaki, M, Kim, JY, Choi, SY, Ko, J & Um, JW 2020, 'Calsyntenin-3 interacts with both a- And b-neurexins in the regulation of excitatory synaptic innervation in specific Schaffer collateral pathways', Journal of Biological Chemistry, vol. 295, no. 27, pp. 9244-9262. https://doi.org/10.1074/jbc.ra120.013077

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T1 - Calsyntenin-3 interacts with both a- And b-neurexins in the regulation of excitatory synaptic innervation in specific Schaffer collateral pathways

AU - Kim, Hyeonho

AU - Kim, Dongwook

AU - Kim, Jinhu

AU - Lee, Hee Yoon

AU - Park, Dongseok

AU - Kang, Hyeyeon

AU - Matsuda, Keiko

AU - Sterky, Fredrik H.

AU - Yuzaki, Michisuke

AU - Kim, Jin Young

AU - Choi, Se Young

AU - Ko, Jaewon

AU - Um, Ji Won

N1 - Publisher Copyright: © 2020 Kim et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc. deletion of Clstn3 in neurons led to drastic reductions in excitatory synapse structures. Finally, adeno-associated virus-mediated expression of Nrxn-binding CST-3 cadherin domains was sufficient to rescue decreased excitatory synapse puncta density in CA1 stratum radiatum layers of Clstn3-deficient mice. Viewed together, our results revise our previous molecular model, showing that Clstn3 directly interacts with SS4-positive Nrxn splice variants to induce presynaptic differentiation, and suggesting synapse-organizing functions of Clstn3 that may control specific synaptic inputs from Schaffer-collateral afferents in the hippocampus.

PY - 2020/7/3

Y1 - 2020/7/3

N2 - Calsyntenin-3 (Clstn3) is a postsynaptic adhesion molecule that induces presynaptic differentiation via presynaptic neurexins (Nrxns), but whether Nrxns directly bind to Clstn3 has been a matter of debate. Here, using LC-MS/MS-based protein analysis, confocal microscopy, RNAscope assays, and electrophysiological recordings, we show that b-Nrxns directly interact via their LNS domain with Clstn3 and Clstn3 cadherin domains. Expression of splice site 4 (SS4) insert-positive b-Nrxn variants, but not insert-negative variants, reversed the impaired Clstn3 synaptogenic activity observed in Nrxn-deficient neurons. Consistently, Clstn3 selectively formed complexes with SS4-positive Nrxns in vivo. Neuron-specific Clstn3 deletion caused significant reductions in number of excitatory synaptic inputs. Moreover, expression of Clstn3 cadherin domains in CA1 neurons of Clstn3 conditional knockout mice rescued structural deficits in excitatory synapses, especially within the stratum radiatum layer. Collectively, our results suggest that Clstn3 links to SS4-positive Nrxns to induce presynaptic differentiation and orchestrate excitatory synapse development in specific hippocampal neural circuits, including Schaffer collateral afferents.

AB - Calsyntenin-3 (Clstn3) is a postsynaptic adhesion molecule that induces presynaptic differentiation via presynaptic neurexins (Nrxns), but whether Nrxns directly bind to Clstn3 has been a matter of debate. Here, using LC-MS/MS-based protein analysis, confocal microscopy, RNAscope assays, and electrophysiological recordings, we show that b-Nrxns directly interact via their LNS domain with Clstn3 and Clstn3 cadherin domains. Expression of splice site 4 (SS4) insert-positive b-Nrxn variants, but not insert-negative variants, reversed the impaired Clstn3 synaptogenic activity observed in Nrxn-deficient neurons. Consistently, Clstn3 selectively formed complexes with SS4-positive Nrxns in vivo. Neuron-specific Clstn3 deletion caused significant reductions in number of excitatory synaptic inputs. Moreover, expression of Clstn3 cadherin domains in CA1 neurons of Clstn3 conditional knockout mice rescued structural deficits in excitatory synapses, especially within the stratum radiatum layer. Collectively, our results suggest that Clstn3 links to SS4-positive Nrxns to induce presynaptic differentiation and orchestrate excitatory synapse development in specific hippocampal neural circuits, including Schaffer collateral afferents.

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SN - 0021-9258

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JF - Journal of Biological Chemistry

IS - 27

ER -

Calsyntenin-3 interacts with both a- And b-neurexins in the regulation of excitatory synaptic innervation in specific Schaffer collateral pathways

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