Phosphorylation of the AMPA receptor GluA1 subunit regulates memory load capacity

Laura Olivito, Paola Saccone, Valentina Perri, Julia L. Bachman, Paola Fragapane, Andrea Mele, Richard L. Huganir, Elvira De Leonibus

Research output: Contribution to journalArticle

Abstract

Memory capacity (MC) refers to the number of elements one can maintain for a short retention interval. The molecular mechanisms underlying MC are unexplored. We have recently reported that mice as well as humans have a limited MC, which is reduced by hippocampal lesions. Here, we addressed the molecular mechanisms supporting MC. GluA1 AMPA-receptors (AMPA-R) mediate the majority of fast excitatory synaptic transmission in the brain and are critically involved in memory. Phosphorylation of GluA1 at serine residues S831 and S845 is promoted by CaMKII and PKA, respectively, and regulates AMPA-R function in memory duration. We hypothesized that AMPA-R phosphorylation may also be a key plastic process for supporting MC because it occurs in a few minutes, and potentiates AMPA-R ion channel function. Here, we show that knock-in mutant mice that specifically lack both of S845 and S831 phosphorylation sites on the GluA1 subunit had reduced MC in two different behavioral tasks specifically designed to assess MC in mice. This demonstrated a causal link between AMPA-R phosphorylation and MC. We then showed that information load regulates AMPA-R phosphorylation within the hippocampus, and that an overload condition associated with impaired memory is paralleled by a lack of AMPA-R phosphorylation. Accordingly, we showed that in conditions of high load, but not of low load, the pharmacological inhibition of the NMDA–CaMKII–PKA pathways within the hippocampus prevents memory as well as associated AMPA-R phosphorylation. These data provide the first identified molecular mechanism that regulates MC.

Original languageEnglish (US)
Pages (from-to)591-603
Number of pages13
JournalBrain Structure and Function
Volume221
Issue number1
DOIs
StatePublished - Jan 1 2016

Keywords

  • AMPA-receptors phosphorylation
  • Hippocampus
  • Long-term memory
  • Protein kinases
  • Working memory capacity

ASJC Scopus subject areas

  • Anatomy
  • Neuroscience(all)
  • Histology

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  • Cite this

    Olivito, L., Saccone, P., Perri, V., Bachman, J. L., Fragapane, P., Mele, A., Huganir, R. L., & De Leonibus, E. (2016). Phosphorylation of the AMPA receptor GluA1 subunit regulates memory load capacity. Brain Structure and Function, 221(1), 591-603. https://doi.org/10.1007/s00429-014-0927-1