Splice‐dependent trans‐synaptic PTP δ– IL 1 RAPL 1 interaction regulates synapse formation and non‐ REM sleep

Abstract

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

Translational changes induced by acute sleep deprivation uncovered by TRAP-Seq

“…For many genes, including those associated with learning and memory or sleep, alternative splicing generates multiple mRNA transcripts [ 47 – 50 ]. However, it can be difficult to determine whether the products of differential splicing seen at the transcript level are translated.…”

SHANK2 mutations impair apoptosis, proliferation and neurite outgrowth during early neuronal differentiation in SH-SY5Y cells

“…10 and 11 ). PVDF membranes (Millipore) were probed with rabbit polyclonal β3-Tubulin 53 (1:20,000; Abcam, ab18207, knockout validated), sheep anti-SHANK2 31 (1:2,500; R&D Systems, AF7035), rabbit anti-GRIN2B 54 (1:1,000; Abcam, ab65783), mouse anti-PSD95 55 , 56 (1:500; NeuroMab, 75–028, knockout validated), rabbit anti-Synaptophysin 57 (1:7,500; Abcam, ab32127, knockout validated), mouse anti-GAPDH 58 (1:10,000; Novus Biologicals, NB300-328), mouse anti-Nestin 59 (1:2,500; Abcam, ab22035), rabbit anti-AKT 45 (1:1,000; Cell Signaling Technology, 9272), mouse anti p-AKT(Ser473) 45 , 60 (1:1,000; Cell Signaling Technology, 4051) and rabbit anti-APP 45 (1:500, Abcam, ab126732, knockout validated).…”

Intact synapse structure and function after combined knockout of PTPδ, PTPσ, and LAR

“…Together, these data challenge the model that LAR-RPTPs are master synapse organizers ( Dunah et al, 2005 ; Fukai and Yoshida, 2020 ; Han et al, 2018 ; Han et al, 2020a ; Han et al, 2020b ; Kwon et al, 2010 ; Takahashi and Craig, 2013 ; Um and Ko, 2013 ; Yim et al, 2013 ). It remains possible that LAR-RPTPs control assembly of a specific subset of synapses, which may explain why PTPδ ablation causes modest layer-specific impairments of synaptic strength ( Park et al, 2020 ).…”

“…In mice, RNAi-mediated knockdown of LAR-RPTPs or deletion of PTPσ caused generalized loss of synapse markers and defective synaptic transmission ( Dunah et al, 2005 ; Han et al, 2018 ; Han et al, 2020a ; Han et al, 2020b ), leading to the model that LAR-RPTPs control synapse formation. Furthermore, mild synaptic and behavioral defects were observed in single gene constitutive knockouts ( Elchebly et al, 1999 ; Horn et al, 2012 ; Park et al, 2020 ; Uetani et al, 2000 ; Wallace et al, 1999 ). Contrasting the RNAi-based analyses, however, a recent study used conditional mouse gene targeting to ablate PTPδ, PTPσ, and LAR, and found no overt defects in neurotransmitter release ( Sclip and Südhof, 2020 ), thereby questioning the general role of LAR-RPTPs in synapse assembly.…”