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

  1. Kevin P Koster
  2. Walter Francesconi
  3. Fulvia Berton
  4. Sami Alahmadi
  5. Roshan Srinivas
  6. Akira Yoshii  Is a corresponding author
  1. University of Illinois at Chicago, United States

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.

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All data generated or analysed during this study are included in the manuscript.

Article and author information

Author details

  1. Kevin P Koster

    Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2935-3427
  2. Walter Francesconi

    Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Fulvia Berton

    Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Sami Alahmadi

    Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Roshan Srinivas

    Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Akira Yoshii

    Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, United States
    For correspondence
    ayoshii@uic.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8305-006X

Funding

University of Illinois at Chicago

  • Akira Yoshii

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal procedures were performed in accordance with the guidelines of the University of Illinois of Chicago Institutional Animal Care and Use Committee. All animals were handled and treated as outlined under the Institutional Animal Care and Use Committee (IACUC) protocol (#17-209). All efforts were made to minimize animal suffering.

Reviewing Editor

  1. Yukiko Goda, RIKEN, Japan

Publication history

  1. Received: July 21, 2018
  2. Accepted: March 31, 2019
  3. Accepted Manuscript published: April 4, 2019 (version 1)
  4. Version of Record published: April 15, 2019 (version 2)

Copyright

© 2019, Koster et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Kevin P Koster
  2. Walter Francesconi
  3. Fulvia Berton
  4. Sami Alahmadi
  5. Roshan Srinivas
  6. Akira Yoshii
(2019)
Developmental NMDA receptor dysregulation in the infantile neuronal ceroid lipofuscinosis mouse model
eLife 8:e40316.
https://doi.org/10.7554/eLife.40316