Splice-dependent trans-synaptic PTPδ–IL1RAPL1 interaction regulates synapse formation and non-REM sleep

Alternative splicing regulates trans-synaptic adhesions and synapse development, but supporting in vivo evidence is limited. PTPδ, a receptor tyrosine phosphatase adhering to multiple synaptic adhesion molecules, is associated with various neuropsychiatric disorders; however, its in vivo functions remain unclear. Here, we show that PTPδ is mainly present at excitatory presynaptic sites by endogenous PTPδ tagging. Global PTPδ deletion in mice leads to input-specific decreases in excitatory synapse development and strength. This involves tyrosine dephosphorylation and synaptic loss of IL1RAPL1, a postsynaptic partner of PTPδ requiring the PTPδ-meA splice insert for binding. Importantly, PTPδ-mutant mice lacking the PTPδ-meA insert, and thus lacking the PTPδ interaction with IL1RAPL1 but not other postsynaptic partners, recapitulate biochemical and synaptic phenotypes of global PTPδ-mutant mice. Behaviorally, both global and meA-specific PTPδ-mutant mice display abnormal sleep behavior and non-REM rhythms. Therefore, alternative splicing in PTPδ regulates excitatory synapse development and sleep by modulating a specific trans-synaptic adhesion.