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

Kevin P Koster,Akira Yoshii,Roshan Srinivas,Sami Alahmadi,Fulvia Berton,Walter Francesconi

doi:10.7554/elife.40316

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 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.

Highlights

The neuronal ceroid lipofuscinoses (NCLs) are a class of individually rare, primarily autosomal recessive, neurodegenerative diseases occurring in an estimated 2 to 4 of 100,000 live births (Nita et al, 2016)
We found impeded developmental N-methyl-D-aspartate receptor (NMDAR) subunit switch from GluN2B to GluN2A in Ppt1-/- mice compared to wild-type (WT)
To understand synaptic dysregulation in CLN1 disease, we utilized the visual cortex of Ppt1-/- animals as a model system

Summary

Introduction

The neuronal ceroid lipofuscinoses (NCLs) are a class of individually rare, primarily autosomal recessive, neurodegenerative diseases occurring in an estimated 2 to 4 of 100,000 live births (Nita et al, 2016). While lipofuscin accumulates in all cells of affected individuals, it deposits most robustly in neurons. This accumulation is concurrent with rapid and progressive neurodegeneration, of thalamic and primary sensory cortical areas (Bible et al, 2004; Kielar et al, 2007). The infantile form of disease, CLN1, presents as early as 6 months of age with progressive psychomotor deterioration, seizure, and death at approximately 5 years of age (Haltia, 2006; Jalanko and Braulke, 2009; Nita et al, 2016).

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