Kim Seoyeong, Shin Jae Jin, Kang Muwon, Yang Yeji, Cho Yi Sul, Paik Hyojung, Kim Jimin, Yi Yunho, Lee Suho, Koo Hei Yeun, Bok Jinwoong, Bae Yong Chul, Kim Jin Young, Kim Eunjoon
Department of Biological Sciences, Korea Advanced Institute for Science and Technology (KAIST), Daejeon, 34141, Korea.
Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon, 34141, Korea.
Nat Commun. 2025 May 13;16(1):4415. doi: 10.1038/s41467-025-59685-3.
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.
由PTPRD编码的蛋白酪氨酸磷酸酶δ（PTPδ）与多种神经、精神和神经发育障碍有关，但其潜在机制仍不清楚。PTPδ通过跨突触与多种突触后黏附分子相互作用，这涉及其细胞外可变剪接的小外显子meA和meB。虽然已在体内研究了PTPδ-meA的功能，但尚未对PTPδ-meB进行研究。在此，我们报告，与纯合PTPδ-meA突变小鼠不同，纯合PTPδ-meB突变（Ptprd-meB）小鼠出生后早期存活率显著降低。杂合Ptprd-meB雄性小鼠表现出行为异常，齿状回颗粒细胞（DG-GCs）中的兴奋性突触密度和传递降低。蛋白质组学分析确定含meB的PTPδ的已知跨突触伴侣IL1RAP的突触后密度水平降低。相应地，IL1RAP突变小鼠在DG-GCs中的兴奋性突触传递降低。IL1RAP表达极少的Ptprd-meB DG中间神经元表现出兴奋性突触密度和传递增加。因此，PTPδ-meB对存活、突触和行为表型很重要，并以细胞类型特异性和IL1RAP依赖的方式调节兴奋性突触。
