Estradiol-induced increase in novel object recognition requires hippocampal NR2B-containing NMDA receptors - PubMed (original) (raw)

Estradiol-induced increase in novel object recognition requires hippocampal NR2B-containing NMDA receptors

Lindsey C Vedder et al. Hippocampus. 2013 Jan.

Abstract

17β-estradiol (E2), at high circulating levels, enhances learning and memory in many women, making it a clinical treatment for hormone-related cognitive decline in aging. However, the mechanisms stimulated by E2, which are responsible for its cognitive enhancing effects, remain incompletely defined. Using an ovariectomized rat model, we previously reported that increasing plasma E2 enhances the magnitude of long-term potentiation (LTP) at hippocampal CA3-CA1 synapses, which is caused by a selective increase in current mediated by NR2B-containing NMDARs, leading to an increase in the NMDAR/AMPAR ratio. Whether the increase in NR2B current is causally related to the ability of E2 to enhance hippocampal dependent learning and memory has yet to be tested. Here, we find that E2 enhances performance in the novel object recognition (NOR) task with the same time course we previously showed E2 enhances the LTP magnitude, temporally linking the increase in LTP to enhanced learning and memory. Furthermore, using the selective NR2B subunit antagonist Ro25-6981, we find that the E2-enhanced NOR, like the enhanced LTP, requires hippocampal NR2B-containing NMDARs, specifically in area CA1. Finally, using whole-cell recordings and the phosphatase inhibitor orthovanadate, we investigated whether the E2-induced increase in NMDAR current is caused by an increase in the density of synaptic NMDARs and/or an increase in NMDAR subunit phosphorylation. We find that both mechanisms are responsible for the enhanced NMDAR current in E2-treated rats. Our results show that the E2-enhanced NOR requires a functional increase in NR2B-containing NMDARs, a requirement shared with the E2-enhanced LTP magnitude at CA3-CA1 synapses, supporting the hypothesis that the increase in LTP likely contributes to the enhanced learning and memory following an increase in plasma E2 levels.

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Figures

Figure 1

Figure 1. E2-enhanced NOR occurs at 24 and 48, but not at 72 hours post E2 treatment

A. Experimental timeline. B–D, Left. The average percent time spent investigating the right object during training demonstrates no object preference in E2 and V-treated rats at E24, E48 and E72. B–C, Right. Percent time spent with the novel object at E24 and E48 was significantly greater in E2-treated compared to V-treated rats. D, Right. Percent time spent with novel object at E72 was not different between E2 and V-treated rats. Far right arrows represent LTP at CA3-CA1 synapses for respective time points as reported in Smith and McMahon, 2005. + indicates significance from chance at p<0.05. * indicates significance of hormone treatment at p<0.05.

Figure 2

Figure 2. E2-enhanced NOR is prevented by blocking NR2B-containing NMDARs

A1. Experimental timeline. A2. No object preference during training. A3. Systemic RO (5mg/kg) blocks learning and memory in E2-treated animals only. B1. Experimental timeline for intraCA1 infusion of RO. B2. No object preference during training. B3. IntraCA1 RO (0.375µg/1µL) infusion blocks E2-enhanced learning and memory. Importantly, V-treated animals still spend significantly more time on the novel object compared to chance. C. Cannula tip locations for each animal included in behavioral experiments. Inset: Cresyl violet stained hippocampal brain slice showing representative cannula tip placement. Scale bar represents 100µM. D. Infusion of 3.75µg/1µL RO blocks NOR in V-treated animals. + indicates percent time spent on novel object is significant from chance. *p<0.05 comparing E2 Sal and E2 RO.

Figure 3

Figure 3. E2 enhances both phosphorylation of NR2B-containing NMDARs and total NR2B-containing NMDARs in the synapse

A. Representative traces for each group with over-layed responses for each stimulus intensity. B. Normalized whole-cell recordings of evoked NMDAR EPSCs at increasing stimulus intensities from V-treated animals with (closed squares) or without (closed circles) orthovanadate in the pipet solution and E2-treated animals with (open squares) or without (open circles) orthovanadate. The maximum evoked NMDAR current measured in cells from E2-treated animals is significantly increased above that measured in cells from V-treated rats. Orthovanadate has no effect in cells from E2-treated animals, but significantly enhances the maximum current elicited in cells from V-treated animals. ***p<0.0005, ** p<0.005, *p<0.05. C. Cartoon model illustrating differences in NMDAR receptor density and subunit phosphorylation in CA1 pyramidal cells from E2-treated versus control rats, and the lack of effect of orthovanadate in E2 versus control cells due to E2-induced saturation of subunit phosphorylation.

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References

    1. Adams MM, Fink SE, Janssen WG, Shah RA, Morrison JH. Estrogen modulates synaptic N-methyl-D-aspartate receptor subunit distribution in the aged hippocampus. J Comp Neurol. 2004;474(3):419–426. - PubMed
    1. Bi R, Foy MR, Vouimba RM, Thompson RF, Baudry M. Cyclic changes in estradiol regulate synaptic plasticity through the MAP kinase pathway. PNAS. 2001;98(23):13391–13395. - PMC - PubMed
    1. Buckley MJ. The role of the perirhinal cortex and hippocampus in learning, memory, and perception. The Quarterly journal of experimental psychology. B, Comparative and physiological psychology. 2005;58(3–4):246–268. - PubMed
    1. Daniel JM, Dohanich GP. Acetylcholine mediates the estrogen-induced increase in nmda receptor binding in ca1 of the hippocampus and the associated improvement in working memory. J Neurosci. 2001;21(17):6949–6956. - PMC - PubMed
    1. Daniel JM, Hulst JL, Lee CD. Role of hippocampal M2 muscarinic receptors in the estrogen-induced enhancement of working memory. Neuroscience. 2005;132(1):57–64. - PubMed

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