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This post-translational modification is critical for synaptic transmission and plasticity. Mutation of the depalmitoylating enzyme palmitoyl-protein thioesterase 1 (PPT1) causes infantile neuronal ceroid lipofuscinosis (CLN1), a pediatric neurodegenerative disease. However, the role of protein depalmitoylation in synaptic maturation is unknown. Therefore, we studied synapse development in Ppt1-\/- mouse visual cortex. We demonstrate that the developmental N-methyl-D-aspartate receptor (NMDAR) subunit switch from GluN2B to GluN2A is stagnated in Ppt1-\/- mice. Correspondingly, Ppt1-\/- neurons exhibit immature evoked NMDAR currents and dendritic spine morphology in vivo. Further, dissociated Ppt1-\/- cultured neurons show extrasynaptic, diffuse calcium influxes and enhanced vulnerability to NMDA-induced excitotoxicity, reflecting the predominance of GluN2B-containing receptors. Remarkably, Ppt1-\/- neurons demonstrate hyperpalmitoylation of GluN2B as well as Fyn kinase, which regulates surface retention of GluN2B. Thus, PPT1 plays a critical role in postsynapse maturation by facilitating the GluN2 subunit switch and proteostasis of palmitoylated proteins.<\/jats:p>","DOI":"10.7554\/elife.40316","type":"journal-article","created":{"date-parts":[[2019,4,4]],"date-time":"2019-04-04T08:01:09Z","timestamp":1554364869000},"source":"Crossref","is-referenced-by-count":42,"title":["Developmental NMDA receptor dysregulation in the infantile neuronal ceroid lipofuscinosis mouse model"],"prefix":"10.7554","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2935-3427","authenticated-orcid":true,"given":"Kevin P","family":"Koster","sequence":"first","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter","family":"Francesconi","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fulvia","family":"Berton","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sami","family":"Alahmadi","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roshan","family":"Srinivas","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8305-006X","authenticated-orcid":true,"given":"Akira","family":"Yoshii","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Illinois at 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