PMID- 30946007 OWN - NLM STAT- MEDLINE DCOM- 20200228 LR - 20200309 IS - 2050-084X (Electronic) IS - 2050-084X (Linking) VI - 8 DP - 2019 Apr 4 TI - Developmental NMDA receptor dysregulation in the infantile neuronal ceroid lipofuscinosis mouse model. LID - 10.7554/eLife.40316 [doi] LID - e40316 AB - Protein palmitoylation and depalmitoylation alter protein function. 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. CI - (c) 2019, Koster et al. FAU - Koster, Kevin P AU - Koster KP AUID- ORCID: 0000-0003-2935-3427 AD - Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, United States. FAU - Francesconi, Walter AU - Francesconi W AD - Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, United States. FAU - Berton, Fulvia AU - Berton F AD - Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, United States. FAU - Alahmadi, Sami AU - Alahmadi S AD - Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, United States. FAU - Srinivas, Roshan AU - Srinivas R AD - Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, United States. FAU - Yoshii, Akira AU - Yoshii A AUID- ORCID: 0000-0001-8305-006X AD - Department of Pediatrics, University of Illinois at Chicago, Chicago, United States. AD - Department of Neurology, University of Illinois at Chicago, Chicago, United States. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190404 PL - England TA - Elife JT - eLife JID - 101579614 RN - 0 (NR2B NMDA receptor) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - EC 3.1.2.- (Thiolester Hydrolases) RN - EC 3.1.2.22 (palmitoyl-protein thioesterase) RN - VH92ICR8HX (N-methyl D-aspartate receptor subtype 2A) SB - IM MH - Animals MH - Disease Models, Animal MH - *Gene Expression Regulation, Developmental MH - Lipoylation MH - Mice MH - Mice, Knockout MH - Neuronal Ceroid-Lipofuscinoses/*physiopathology MH - Protein Processing, Post-Translational MH - Receptors, N-Methyl-D-Aspartate/*metabolism MH - Thiolester Hydrolases/deficiency/*metabolism PMC - PMC6464704 OTO - NOTNLM OT - NMDA OT - depalmitoylation OT - lipofuscinosis OT - mouse OT - neurodevelopment OT - neuroscience OT - palmitoylation COIS- KK, WF, FB, SA, RS, AY No competing interests declared EDAT- 2019/04/05 06:00 MHDA- 2020/02/29 06:00 PMCR- 2019/04/04 CRDT- 2019/04/05 06:00 PHST- 2018/07/21 00:00 [received] PHST- 2019/03/31 00:00 [accepted] PHST- 2019/04/05 06:00 [pubmed] PHST- 2020/02/29 06:00 [medline] PHST- 2019/04/05 06:00 [entrez] PHST- 2019/04/04 00:00 [pmc-release] AID - 40316 [pii] AID - 10.7554/eLife.40316 [doi] PST - epublish SO - Elife. 2019 Apr 4;8:e40316. doi: 10.7554/eLife.40316.