Developmental NMDA receptor dysregulation in the infantile neuronal ceroid lipofuscinosis mouse model.

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 mouse visual cortex. We demonstrate that the developmental N-methyl-D-aspartate receptor (NMDAR) subunit switch from GluN2B to GluN2A is stagnated in mice. Correspondingly, neurons exhibit immature evoked NMDAR currents and dendritic spine morphology in vivo. Further, dissociated cultured neurons show extrasynaptic, diffuse calcium influxes and enhanced vulnerability to NMDA-induced excitotoxicity, reflecting the predominance of GluN2B-containing receptors. Remarkably, 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.