AMPA receptor desensitization mutation results in severe developmental phenotypes and early postnatal lethality

Louisa A. Christie, Theron A. Russell, Jian Xu, Lydia Wood, Gordon M.G. Shepherd, Anis Contractor*

*Corresponding author for this work

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate) receptors desensitize rapidly and completely in the continued presence of their endogenous ligand glutamate; however, it is not clearwhat role AMPA receptor desensitization plays in the brain. We generated a knock-inmouse inwhich a single aminoacid residue,which controls desensitization, was mutated in the GluA2 (GluR2) receptor subunit (GluA2L483Y). This mutation was homozygous lethal. However, mice carrying a single mutated allele, GluA2 L483Y/wt, survived past birth, but displayed severe and progressive neurological deficits including seizures and, ultimately, increased mortality. The expression of the AMPA receptor subunits GluA1 and GluA2 was decreased, whereas NMDA receptor protein expression was increased in GluA2 L483Y/wt mice. Despite this, basal synaptic transmission and plasticity in the hippocampus were largely unaffected, suggesting that neurons preferentially target receptors to synapses to normalize synaptic weight. We found no gross neuroanatomical alterations in GluA2L483Y/wt mice. Moreover, there was no accumulation of AMPA receptor subunits in intracellular compartments, suggesting that folding and assembly of AMPA receptors are not affected by this mutation. Interestingly, EPSC paired pulse ratios in the CA1 were enhanced without a change in synaptic release probability, demonstrating that postsynaptic receptor properties can contribute to facilitation. The dramatic phenotype observed in this study by the introduction of a single amino acid change demonstrates an essential role in vivo for AMPA receptor desensitization.

Original languageEnglish (US)
Pages (from-to)9412-9417
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number20
DOIs
StatePublished - May 18 2010

Keywords

  • GluA2 (GluR2)
  • Hippocampus
  • Knock-in mouse
  • Seizures

ASJC Scopus subject areas

  • General

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