AUTHOR=Chojnacka Magdalena , Beroun Anna , Magnowska Marta , Stawikowska Aleksandra , Cysewski Dominik , Milek Jacek , Dziembowska Magdalena , Kuzniewska Bozena 

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

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=Volume 16 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2023.1258615

DOI=10.3389/fnmol.2023.1258615

ISSN=1662-5099

ABSTRACT=<p>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 <italic>Fmr1</italic> 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 <italic>Fmr1</italic> 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 <italic>Fmr</italic>1 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 <italic>Fmr1</italic> KO mice. Furthermore, we show that <italic>Fmr1</italic> 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<sup>2+−</sup>impermeable receptors in adult <italic>Fmr1</italic> KO synapses.</p>