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<p>PTPδ, encoded by <i>PTPRD</i>, 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 (<i>Ptprd-meB</i><sup><i>–/–</i></sup>) mice show markedly reduced early postnatal survival. Heterozygous <i>Ptprd-meB</i><sup><i>+/–</i></sup> 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. <i>Ptprd-meB</i><sup><i>+/–</i></sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月13日

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  • 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,
  • Eunjoon Kim

摘要

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.