Splice-dependent trans-synaptic PTP?-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. PTP?, 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 PTP? is mainly present at excitatory presynaptic sites by endogenous PTP? tagging. Global PTP? 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 PTP? requiring the PTP?-meA splice insert for binding. Importantly, PTP?-mutant mice lacking the PTP?-meA insert, and thus lacking the PTP??interaction with IL1RAPL1 but not other postsynaptic partners, recapitulate biochemical and synaptic phenotypes of global PTP?-mutant mice. Behaviorally, both global and meA-specific PTP?-mutant mice display abnormal sleep behavior and non-REM rhythms. Therefore, alternative splicing in PTP? regulates excitatory synapse development and sleep by modulating a specific trans-synaptic adhesion.