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

Nat Commun. 2025 May 13;16(1):4415. doi: 10.1038/s41467-025-59685-3.

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.

MeSH terms

  • Alternative Splicing*
  • Animals
  • Behavior, Animal
  • Dentate Gyrus / cytology
  • Dentate Gyrus / metabolism
  • Exons* / genetics
  • Female
  • Interneurons / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2* / genetics
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2* / metabolism
  • Synapses* / metabolism
  • Synaptic Transmission / genetics

Substances

  • Receptor-Like Protein Tyrosine Phosphatases, Class 2