Impaired synaptic incorporation of AMPA receptors in a mouse model of fragile X syndrome

Magdalena Chojnacka; Anna Beroun; Marta Magnowska; Aleksandra Stawikowska; Dominik Cysewski; Jacek Milek; Magdalena Dziembowska; Bozena Kuzniewska

doi:10.3389/fnmol.2023.1258615

Impaired synaptic incorporation of AMPA receptors in a mouse model of fragile X syndrome

Front Mol Neurosci. 2023 Nov 9:16:1258615. doi: 10.3389/fnmol.2023.1258615. eCollection 2023.

Authors

Magdalena Chojnacka¹, Anna Beroun², Marta Magnowska¹, Aleksandra Stawikowska¹, Dominik Cysewski³, Jacek Milek¹, Magdalena Dziembowska¹, Bozena Kuzniewska¹

Affiliations

¹ Laboratory of Molecular Basis of Synaptic Plasticity, Centre of New Technologies, University of Warsaw, Warsaw, Poland.
² Laboratory of Neuronal Plasticity, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland.
³ Clinical Research Centre, Medical University of Bialystok, Bialystok, Poland.

Abstract

Fragile X syndrome (FXS) is the most common monogenetic cause of inherited intellectual disability and autism in humans. One of the well-characterized molecular phenotypes of Fmr1 KO mice, a model of FXS, is increased translation of synaptic proteins. Although this upregulation stabilizes in adulthood, abnormalities during the critical period of plasticity have long-term effects on circuit formation and synaptic properties. Using high-resolution quantitative proteomics of synaptoneurosomes isolated from the adult, developed brains of Fmr1 KO mice, we show a differential abundance of proteins regulating the postsynaptic receptor activity of glutamatergic synapses. We investigated the AMPA receptor composition and shuttling in adult Fmr1 KO and WT mice using a variety of complementary experimental strategies such as surface protein crosslinking, immunostaining of surface receptors, and electrophysiology. We discovered that the activity-dependent synaptic delivery of AMPARs is impaired in adult Fmr1 KO mice. Furthermore, we show that Fmr1 KO synaptic AMPARs contain more GluA2 subunits that can be interpreted as a switch in the synaptic AMPAR subtype toward an increased number of Ca^2+-impermeable receptors in adult Fmr1 KO synapses.

Keywords: AMPA receptors; FXS; Fmr1 KO; GluA2; brain; synaptic plasticity.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was mainly supported by NCN Grant 2019/35/B/NZ4/04355 for MD.