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