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[Q. Neuroscience-24]
Splice-dependent trans-synaptic PTPδ–IL1RAPL1 interaction
regulates synapse formation and non-REM sleep
Seoyeong Kim²˙#, Haram Park¹˙#, Yeonsoo Choi¹˙#, Hwajin Jung¹˙#, Suho Lee¹, Hyemin Han³, Hanseul
Kweon², Suwon Kang², Woong Seob Sim², Frank Koopmans⁴˙⁵, Esther Yang⁶, Hyun Kim⁶, August B Smit⁵,
Yong Chul Bae³, Eunjoon Kim¹˙²˙*
¹Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon 34141, Korea, ²Department of
Biological Sciences, Korea Advanced Institute for Science and Technology (KAIST), Daejeon 34141, Korea,
³Department of Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu 41940,
Korea, ⁴Department of Functional Genomics, CNCR, VU University and UMC Amsterdam, Amsterdam 1081,
Netherlands, ⁵Department of Molecular and Cellular Neurobiology, CNCR, VU University and UMC Amsterdam,
Amsterdam 1081, Netherlands, ⁶Department of Anatomy and Division of Brain Korea 21, Biomedical Science,
College of Medicine, Korea University, Seoul 02841, Korea
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.
