2. Academic Validation
  3. Paralogs of Slitrk cell adhesion molecules configure excitatory synapse specificity via distinct cellular mechanisms

Paralogs of Slitrk cell adhesion molecules configure excitatory synapse specificity via distinct cellular mechanisms

  • PLoS Biol. 2025 Dec 18;23(12):e3003576. doi: 10.1371/journal.pbio.3003576.
Dongwook Kim 1 2,  Byeongchan Kim 1,  Jinhu Kim 1 2,  Na-Young Seo 1 3,  Hyeonho Kim 1 2,  Kyung Ah Han 1 2,  Jubeen Yoon 4 5 6,  Christian P Macks 6,  Joris de Wit 7 8,  Chang Ho Sohn 6,  Kea Joo Lee 3,  Ji Won Um 1 2,  Jaewon Ko 1 2
Affiliations

Affiliations

  • 1 Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Korea.
  • 2 Center for Synapse Diversity and Specificity, DGIST, Daegu, Korea.
  • 3 Neural Circuits Research Group, Korea Brain Research Institute (KBRI), Daegu, Korea.
  • 4 Department of NanoBiomedical Engineering (NanoBME), Advanced Science Institute, Yonsei University, Seoul, Korea.
  • 5 Center for Nanomedicine, Institute for Basic Science, Seoul, Korea.
  • 6 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.
  • 7 VIB Center for Brain & Disease Research, Leuven, Belgium.
  • 8 KU Leuven, Department of Neurosciences, Leuven Brain Institute, Leuven, Belgium.
PMID: 41411344 DOI: 10.1371/journal.pbio.3003576
Abstract

Vertebrate neural circuit properties are shaped by synaptic cell adhesion molecules (CAMs). CAMs often have multiple paralogs but the possible redundancy of such paralogs remains underexplored. Using circuit-specific conditional knockout (cKO) mice deficient for Slitrk1 and Slitrk2, we show that these paralogs lack specific laminar expression in mature hippocampal neurons but divergently guide the specificity of neural circuits in distinct hippocampal subfields. Slitrk1 and Slitrk2 regulate distinct facets of excitatory synaptic properties in a microcircuit-dependent manner through binding to LAR-RPTPs, and additionally in the case of Slitrk2, through binding to PDZ domain-containing proteins and TrkB. Analyses of Slitrk2 V89M knock-in mice revealed that this schizophrenia-associated substitution acts uniquely as a loss-of-function mutation in some microcircuits to impair excitatory synaptic transmission, asynchronous release, and spatial reference memory. These findings demonstrate that even structurally and biochemically similar synaptic CAMs can play distinct roles in specifying neural circuit architecture.

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