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Neuroscience. 2018 Dec 1;394:303-315. doi: 10.1016/j.neuroscience.2018.09.021.

Estrogen Alters the Synaptic Distribution of Phospho-GluN2B in the Dorsolateral Prefrontal Cortex While Promoting Working Memory in Aged Rhesus Monkeys.

Author information

1
Fishberg Department of Neuroscience and Kastor Neurobiology of Aging Laboratories, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
2
Fishberg Department of Neuroscience and Kastor Neurobiology of Aging Laboratories, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; California National Primate Research Center, Davis, CA 95616, United States.
3
National Institute on Aging, Laboratory of Behavioral Neuroscience, Baltimore, MD 21224, United States.
4
Fishberg Department of Neuroscience and Kastor Neurobiology of Aging Laboratories, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Department of Geriatrics and Palliative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; California National Primate Research Center, Davis, CA 95616, United States; Department of Neurology, School of Medicine, University of California, Davis, CA 95616, United States. Electronic address: jhmorrison@ucdavis.edu.

Abstract

Age- and menopause-related deficits in working memory can be partially restored with estradiol replacement in women and female nonhuman primates. Working memory is a cognitive function reliant on persistent firing of dorsolateral prefrontal cortex (dlPFC) neurons that requires the activation of GluN2B-containing glutamate NMDA receptors. We tested the hypothesis that the distribution of phospho-Tyr1472-GluN2B (pGluN2B), a predominant form of GluN2B seen at the synapse, is sensitive to aging or estradiol treatment and coupled to working memory performance. First, ovariectomized young and aged rhesus monkeys (Macaca mulatta) received long-term cyclic vehicle (V) or estradiol (E) treatment and were tested on the delayed response (DR) test of working memory. Then, serial section electron microscopic immunocytochemistry was performed to quantitatively assess the subcellular distribution of pGluN2B. While the densities of pGluN2B immunogold particles in dlPFC dendritic spines were not different across age or treatment groups, the percentage of gold particles located within the synaptic compartment was significantly lower in aged-E monkeys compared to young-E and aged-V monkeys. On the other hand, the percentage of pGluN2B gold particles in the spine cytoplasm was decreased with E treatment in young, but increased with E in aged monkeys. In aged monkeys, DR average accuracy inversely correlated with the percentage of synaptic pGluN2B, while it positively correlated with the percentage of cytoplasmic pGluN2B. Together, E replacement may promote cognitive health in aged monkeys, in part, by decreasing the relative representation of synaptic pGluN2B and potentially protecting the dlPFC from calcium toxicity.

KEYWORDS:

Area 46; Tyr-1472; aging; delayed response; estradiol; menopause

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