| First Author | Koster KP | Year | 2019 |
| Journal | Elife | Volume | 8 |
| PubMed ID | 30946007 | Mgi Jnum | J:274689 |
| Mgi Id | MGI:6304015 | Doi | 10.7554/eLife.40316 |
| Citation | Koster KP, et al. (2019) Developmental NMDA receptor dysregulation in the infantile neuronal ceroid lipofuscinosis mouse model. Elife 8:e40316 |
| abstractText | 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. |
