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

초록

PTP delta, encoded by PTPRD, is implicated in various neurological, psychiatric, and neurodevelopmental disorders, but the underlying mechanisms remain unclear. PTP delta trans-synaptically interacts with multiple postsynaptic adhesion molecules, which involves its extracellular alternatively spliced mini-exons, meA and meB. While PTP delta-meA functions have been studied in vivo, PTP delta-meB has not been studied. Here, we report that, unlike homozygous PTP delta-meA-mutant mice, homozygous PTP delta-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 PTP delta. 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, PTP delta-meB is important for survival, synaptic, and behavioral phenotypes and regulates excitatory synapses in cell-type-specific and IL1RAP-dependent manners.

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