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

Haram Park,Seoyeong Kim,August B Smit,Hyemin Han,Eunjoon Kim,Frank Koopmans,Yong Chul Bae,Yeonsoo Choi,Esther Yang,Hwajin Jung,Woong Seob Sim,Hyun Kim,Hanseul Kweon,Suwon Kang,Suho Lee

doi:10.15252/embj.2019104150

Abstract

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.

Highlights

IntroductionScheiffele, 2010; Siddiqui & Craig, 2011; de Wit & Ghosh, 2016; Sudhof, 2017, 2018; Yuzaki, 2018; Kurshan & Shen, 2019)
Synaptic cell adhesion molecules (CAMs) mediate trans-synaptic adhesions to regulate synapse development and function (Shen &Scheiffele, 2010; Siddiqui & Craig, 2011; de Wit & Ghosh, 2016; Sudhof, 2017, 2018; Yuzaki, 2018; Kurshan & Shen, 2019)
The signals were strong in cortical layer I, the corpus callosum, and the anterior commissure—all of which feature dense axonal tracts—as well as the stratum lacunosum moleculare (SLM) and dentate gyrus molecular (DG-MO) layer of the hippocampus, upper cortical layers, thalamus, and the reticulate nucleus of the thalamus (TRN)

Summary

Introduction

Scheiffele, 2010; Siddiqui & Craig, 2011; de Wit & Ghosh, 2016; Sudhof, 2017, 2018; Yuzaki, 2018; Kurshan & Shen, 2019) These trans-synaptic adhesions are often themselves regulated by small splice inserts present on the extracellular regions of synaptic adhesion molecules. Alternative splicing has been shown to regulate aspects of synapse development and function, including the specificity and strength of trans-synaptic adhesions, excitatory or inhibitory synaptic localization of adhesion molecules, and transsynaptic control of the responses of postsynaptic receptors, such as NMDA receptors (NMDARs) and AMPA receptors (AMPARs) (Boucard et al, 2005; Chih et al, 2006; Graf et al, 2006; Aoto et al, 2013; Dai et al, 2019). Splice inserts on neuroligins regulate contacts of neuroligins with glutamatergic and GABAergic nerve terminals (Chih et al, 2006) as well as the binding preference of neuroligin-1 for a- or b-neurexins (Boucard et al, 2005)

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Results

Conclusion