The Tyrosine Phosphatase STEP Is Involved in Age-Related Memory Decline

David Castonguay, Julien Dufort-Gervais, Caroline Ménard, Manavi Chatterjee, Rémi Quirion, Bruno Bontempi, Jay S. Schneider, Amy F.T. Arnsten, Angus C. Nairn, Christopher M. Norris, Guylaine Ferland, Erwan Bézard, Pierrette Gaudreau, Paul J. Lombroso, Jonathan Brouillette

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Cognitive disabilities that occur with age represent a growing and expensive health problem. Age-associated memory deficits are observed across many species, but the underlying molecular mechanisms remain to be fully identified. Here, we report elevations in the levels and activity of the striatal-enriched phosphatase (STEP) in the hippocampus of aged memory-impaired mice and rats, in aged rhesus monkeys, and in people diagnosed with amnestic mild cognitive impairment (aMCI). The accumulation of STEP with aging is related to dysfunction of the ubiquitin-proteasome system that normally leads to the degradation of STEP. Higher level of active STEP is linked to enhanced dephosphorylation of its substrates GluN2B and ERK1/2, CREB inactivation, and a decrease in total levels of GluN2B and brain-derived neurotrophic factor (BDNF). These molecular events are reversed in aged STEP knockout and heterozygous mice, which perform similarly to young control mice in the Morris water maze (MWM) and Y-maze tasks. In addition, administration of the STEP inhibitor TC-2153 to old rats significantly improved performance in a delayed alternation T-maze memory task. In contrast, viral-mediated STEP overexpression in the hippocampus is sufficient to induce memory impairment in the MWM and Y-maze tests, and these cognitive deficits are reversed by STEP inhibition. In old LOU/C/Jall rats, a model of healthy aging with preserved memory capacities, levels of STEP and GluN2B are stable, and phosphorylation of GluN2B and ERK1/2 is unaltered. Altogether, these data suggest that elevated levels of STEP that appear with advancing age in several species contribute to the cognitive declines associated with aging. The molecular changes leading to memory deficits during aging remain to be fully identified. Castonguay et al. provide genetic, behavioral, and molecular evidence that accumulation of the phosphatase STEP is a common molecular event that oppose synaptic strengthening and contributes to age-related memory deficits in mice, rats, monkeys, and humans.

Original languageEnglish
Pages (from-to)1079-1089.e4
JournalCurrent Biology
Volume28
Issue number7
DOIs
StatePublished - Apr 2 2018

Bibliographical note

Publisher Copyright:
© 2018 Elsevier Ltd

Keywords

  • aging
  • animal behaviors
  • animal models
  • hippocampus
  • memory
  • phosphatase STEP

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology
  • General Agricultural and Biological Sciences

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