CPEB3-dependent increase in GluA2 subunits impairs excitatory transmission onto inhibitory interneurons in a mouse model of fragile X

Cell Rep. 2022 Jun 7;39(10):110853. doi: 10.1016/j.celrep.2022.110853.


Fragile X syndrome (FXS) is a leading cause of inherited intellectual disability and autism. Whereas dysregulated RNA translation in Fmr1 knockout (KO) mice, a model of FXS, is well studied, little is known about aberrant transcription. Using single-molecule mRNA detection, we show that mRNA encoding the AMPAR subunit GluA2 (but not GluA1) is elevated in dendrites and at transcription sites of hippocampal neurons of Fmr1 KO mice, indicating elevated GluA2 transcription. We identify CPEB3, a protein implicated in memory consolidation, as an upstream effector critical to GluA2 mRNA expression in FXS. Increased GluA2 mRNA is translated into an increase in GluA2 subunits, a switch in synaptic AMPAR phenotype from GluA2-lacking, Ca2+-permeable to GluA2-containing, Ca2+-impermeable, reduced inhibitory synaptic transmission, and loss of NMDAR-independent LTP at glutamatergic synapses onto CA1 inhibitory interneurons. These factors could contribute to an excitatory/inhibitory imbalance-a common theme in FXS and other autism spectrum disorders.

Keywords: AMPA receptors; CP: Neuroscience; dendrites; mRNA localization; single-molecule FISH; transcription; transcription sites.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Fragile X Mental Retardation Protein / metabolism
  • Fragile X Syndrome* / genetics
  • Interneurons / metabolism
  • Mice
  • Mice, Knockout
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins* / genetics
  • Receptors, AMPA* / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Synapses / metabolism


  • Cpeb3 protein, mouse
  • Fmr1 protein, mouse
  • RNA, Messenger
  • RNA-Binding Proteins
  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • Fragile X Mental Retardation Protein