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.
|State||Published - Apr 2 2018|
Bibliographical noteFunding Information:
We thank laboratory members for helpful discussions and critical reading of the manuscript. We thank Jian Xu for providing the GST-GluN2B construct and Mitchell Powell for technical assistance. We thank Dr. Marilee Ogren for critical reading of the manuscript. Thank you also to Dr. Erin Abner at the Sanders-Brown Center on Aging for assistance with human case histories. This work was funded by a FRQS and Hôpital du Sacré-Coeur de Montréal (HSCM) grant (J.B.), NIH grants MH091037 and MH052711 (P.J.L.), AG047270 (A.C.N.), and AG024190, AG027297, and AG028383, and Center's ADC grant P30AG028383 (C.M.N.). This research was supported by an unrestricted grant from Motac Holding (J.S.S. and E.B.), and CNRS and ANR-10-MALZ-002 grants (B.B.). This project was funded by grants from the Canadian Institutes of Health Research (CIHR) (R.Q.) and the Quebec Network for Research on Aging (a network funded by Fonds de Recherche du Québec – Santé) (P.G. and G.F.). C.M. holds a postdoctoral fellowship from CIHR.
© 2018 Elsevier Ltd
- animal behaviors
- animal models
- phosphatase STEP
ASJC Scopus subject areas
- Neuroscience (all)
- Biochemistry, Genetics and Molecular Biology (all)
- Agricultural and Biological Sciences (all)