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bioRxiv · 10.1101/390732

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

Koster, K. P.·Francesconi, W.·Berton, F.·Alahmadi, S.·Srinivas, R.·Yoshii, A.
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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.

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Koster, K. P., Francesconi, W., Berton, F., Alahmadi, S., Srinivas, R., Yoshii, A.. 2018-08-13. NMDA Receptor Dysregulation by Defective Depalmitoylation in the Infantile Neuronal Ceroid Lipofuscinosis Mouse Model. https://doi.org/10.1101/390732

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