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

Yuko Hara, Johanna L. Crimins, Rishi Puri, Athena C.J. Wang, Sarah E. Motley, Frank Yuk, Tiffany M. Ramos, William G.M. Janssen, Peter R. Rapp, John Morrison

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
JournalNeuroscience
DOIs
StateAccepted/In press - Jan 1 2018

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Prefrontal Cortex
Macaca mulatta
Short-Term Memory
Haplorhini
Estrogens
Estradiol
Gold
Dendritic Spines
Glutamate Receptors
Therapeutics
Menopause
N-Methyl-D-Aspartate Receptors
Synapses
Cognition
Primates
Cytoplasm
Spine
Immunohistochemistry
Electrons
Calcium

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Estrogen Alters the Synaptic Distribution of Phospho-GluN2B in the Dorsolateral Prefrontal Cortex While Promoting Working Memory in Aged Rhesus Monkeys. / Hara, Yuko; Crimins, Johanna L.; Puri, Rishi; Wang, Athena C.J.; Motley, Sarah E.; Yuk, Frank; Ramos, Tiffany M.; Janssen, William G.M.; Rapp, Peter R.; Morrison, John.

In: Neuroscience, 01.01.2018.

Research output: Contribution to journalArticle

Hara, Yuko ; Crimins, Johanna L. ; Puri, Rishi ; Wang, Athena C.J. ; Motley, Sarah E. ; Yuk, Frank ; Ramos, Tiffany M. ; Janssen, William G.M. ; Rapp, Peter R. ; Morrison, John. / Estrogen Alters the Synaptic Distribution of Phospho-GluN2B in the Dorsolateral Prefrontal Cortex While Promoting Working Memory in Aged Rhesus Monkeys. In: Neuroscience. 2018.
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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.",
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AU - Hara, Yuko

AU - Crimins, Johanna L.

AU - Puri, Rishi

AU - Wang, Athena C.J.

AU - Motley, Sarah E.

AU - Yuk, Frank

AU - Ramos, Tiffany M.

AU - Janssen, William G.M.

AU - Rapp, Peter R.

AU - Morrison, John

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N2 - 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.

AB - 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.

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