Novel IL1RAPL1mutations associated with intellectual disability impair synaptogenesis MarianaRamos-Brossier1,{, CaterinaMontani2,{, NicolasLebrun1, LauraGritti2, ChristelleMartin3, ChristineSeminatore-Nole1,AurelieToussaint4, SarahMoreno1,KarinePoirier1,O

Mutations in interleukin-1 receptor accessory protein like 1 (IL1RAPL1) gene have been associated with non-syndromic intellectualdisability (ID)andautismspectrumdisorder.Thisprotein interactswithsynapticpartners like PSD-95 andPTPd, regulating the formation and function of excitatory synapses. The aimof thisworkwas to characterize the synaptic consequences of three IL1RAPL1mutations, two novel causing the deletion of exon 6 (Dex6) and one point mutation (C31R), identified in patients with ID. Using immunofluorescence and electro-physiological recordings, we examined the effects of IL1RAPL1mutant over-expression on synapse formation and function in cultured rodent hippocampal neurons. Dex6 but not C31R mutation leads to IL1RAPL1 protein instability and mislocalization within dendrites. Analysis of different markers of excitatory synapses and sEPSC recording revealed that both mutants fail to induce pre- and post-synaptic differentiation, contrary t