Calsyntenin-3 interacts with both α- and β-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

Research output: Contribution to journalArticlepeer-review

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 β-Nrxns directly interact via their LNS domain with Clstn3 and Clstn3 cadherin domains. Expression of splice site 4 (SS4) insert-positive β-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 languageEnglish
Pages (from-to)9244-9262
Number of pages19
JournalThe Journal of biological chemistry
Volume295
Issue number27
DOIs
Publication statusPublished - 2020 Jul 3

Keywords

  • adhesion
  • alternative splicing
  • calsyntenin-3 (Clstn3)
  • development
  • hippocampus
  • neurexin (Nrxn)
  • Schaffer collateral afferent
  • structure-function
  • synapse
  • synapse development
  • synaptic adhesion
  • synaptic excitation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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