Alternatively spliced mini-exon B in PTPδ regulates excitatory synapses through cell-type-specific trans-synaptic PTPδ-IL1RAP interaction

Seoyeong Kim, Jae Jin Shin, Muwon Kang, Yeji Yang, Yi Sul Cho, Hyojung Paik, Jimin Kim, Yunho Yi, Suho Lee, Hei Yeun Koo, Jinwoong Bok, Yong Chul Bae, Jin Young Kim and Eunjoon Kim ()
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Seoyeong Kim: Korea Advanced Institute for Science and Technology (KAIST)
Jae Jin Shin: Institute for Basic Science (IBS)
Muwon Kang: Korea Advanced Institute for Science and Technology (KAIST)
Yeji Yang: Korea Advanced Institute for Science and Technology (KAIST)
Yi Sul Cho: Kyungpook National University
Hyojung Paik: Korea Institute of Science and Technology Information (KISTI)
Jimin Kim: Korea Institute of Science and Technology Information (KISTI)
Yunho Yi: Korea Advanced Institute for Science and Technology (KAIST)
Suho Lee: Institute for Basic Science (IBS)
Hei Yeun Koo: Yonsei University College of Medicine
Jinwoong Bok: Yonsei University College of Medicine
Yong Chul Bae: Kyungpook National University
Jin Young Kim: Korea Basic Science Institute (KBSI)
Eunjoon Kim: Korea Advanced Institute for Science and Technology (KAIST)

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract PTPδ, encoded by PTPRD, is implicated in various neurological, psychiatric, and neurodevelopmental disorders, but the underlying mechanisms remain unclear. PTPδ trans-synaptically interacts with multiple postsynaptic adhesion molecules, which involves its extracellular alternatively spliced mini-exons, meA and meB. While PTPδ-meA functions have been studied in vivo, PTPδ-meB has not been studied. Here, we report that, unlike homozygous PTPδ-meA-mutant mice, homozygous PTPδ-meB-mutant (Ptprd-meB–/–) mice show markedly reduced early postnatal survival. Heterozygous Ptprd-meB+/– male mice show behavioral abnormalities and decreased excitatory synaptic density and transmission in dentate gyrus granule cells (DG-GCs). Proteomic analyses identify decreased postsynaptic density levels of IL1RAP, a known trans-synaptic partner of meB-containing PTPδ. Accordingly, IL1RAP-mutant mice show decreased excitatory synaptic transmission in DG-GCs. Ptprd-meB+/– DG interneurons with minimal IL1RAP expression show increased excitatory synaptic density and transmission. Therefore, PTPδ-meB is important for survival, synaptic, and behavioral phenotypes and regulates excitatory synapses in cell-type-specific and IL1RAP-dependent manners.

Date: 2025
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DOI: 10.1038/s41467-025-59685-3

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