NMDA Receptor Dysregulation by Defective Depalmitoylation in the Infantile Neuronal Ceroid Lipofuscinosis Mouse Model

Abstract 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 the stagnation of the developmental N-methyl-D-aspartate receptor (NMDAR) subunit switch from GluN2B to GluN2A in Ppt1-/- mice. Correspondingly, GluN2A-mediated synaptic currents are diminished and Ppt1-/- dendritic spines maintain immature morphology in vivo. Further, GluN2B is hyperpalmitoylated in Ppt1-/- neurons and associated with extrasynaptic, diffuse calcium influxes and enhanced vulnerability to NMDA-induced excitotoxicity. Remarkably, Ppt1-/- neurons treated with palmitoylation inhibitors demonstrate normalized levels of palmitoylated GluN2B and Fyn kinase, reversing susceptibility to excitotoxic insult. Thus, depalmitoylation of GluN2B by PPT1 plays a critical role in postsynapse maturation and pathophysiology of neurodegenerative disease.