Estrogen modulates synaptic <i>N</i>‐methyl‐<scp>D</scp>‐aspartate receptor subunit distribution in the aged hippocampus

Adams, Michelle M.; Fink, Susan E.; Janssen, William G.M.; Shah, Ravi A.; Morrison, John H.

doi:10.1002/cne.20148

Cited by 127 publications

(106 citation statements)

References 41 publications

(71 reference statements)

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“…However, the short time domains of both systemic E2 and intrathecal E2-BSA effects on pLTF expression in our studies argue against these transcriptional mechanisms, and suggest a much faster cascade of effects, perhaps involving altered glutamatergic receptor signaling necessary for pLTF (McGuire et al, 2008). Membrane ER signaling can modulate existing postsynaptic NMDA receptors (Snyder et al, 2011;Zhang et al, 2012) and/or recruit them to active postsynaptic densities (Adams et al, 2004;Smith and McMahon, 2005;Snyder et al, 2011;Potier et al, 2016;Smith et al, 2016). These actions may explain the enhanced phrenic nerve burst response observed during hypoxia with acute E2-BSA treatment, and the corresponding return of pLTF (McGuire et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Nongenomic Actions of 17-β Estradiol Restore Respiratory Neuroplasticity in Young Ovariectomized Female Rats

2017

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Gonadal steroids modulate CNS plasticity, including phrenic long-term facilitation (pLTF), a form of spinal respiratory neuroplasticity resulting in increased phrenic nerve motor output following exposure to acute intermittent hypoxia (aIH; three 5 min episodes, 10.5% O 2 ). Despite the importance of respiratory system neuroplasticity, and its dependence on estrogen in males, little is known about pLTF expression or mechanisms of estrogen signaling in females. Here, we tested the hypotheses that (1) pLTF expression in young, gonadally intact female rats would be expressed during estrous cycle stages in which 17␤-estradiol (E2) is naturally high (e.g., proestrus vs estrus), (2) pLTF would be absent in ovariectomized (OVX) rats and in physiological conditions in which serum progesterone, but not E2, is elevated (e.g., lactating rats, 3-10 d postpartum), and (3) acute E2 administration would be sufficient to restore pLTF in OVX rats. Recordings of phrenic nerve activity in female Sprague Dawley rats (3-4 months) revealed a direct correlation between serum E2 levels and pLTF expression in cycling female rats. pLTF was abolished with OVX, but was re-established by acute E2 replacement (3 h, intraperitoneal). To identify underlying E2 signaling mechanisms, we intrathecally applied BSA-conjugated E2 over the spinal phrenic motor nucleus and found that pLTF expression was restored within 15 min, suggesting nongenomic E2 effects at membrane estrogen receptors. These data are the first to investigate the role of ovarian E2 in young cycling females, and to identify a role for nongenomic estrogen signaling in any form of respiratory system neuroplasticity.

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Section: Discussionmentioning

confidence: 99%

Nongenomic Actions of 17-β Estradiol Restore Respiratory Neuroplasticity in Young Ovariectomized Female Rats

2017

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“…Several mechanisms have been reported by which estrogen acutely and more chronically potentiates memory-related synaptic plasticity in the hippocampus. Estradiol has been shown to increase dendritic spinogenesis in the hippocampus (44,45), increase the expression of NMDA receptor (NMDAR) subunit NR2B (46), and potentiate NMDAR-mediated synaptic activity, including LTP (47,48). The identity of the ER involved in potentiation of synaptic plasticity and memory has not yet been fully confirmed.…”

Section: Discussionmentioning

confidence: 99%

Estrogens directly potentiate neuronal L-type Ca ²⁺ channels

Sarkar

Huang

Logan

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

101

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L-type voltage-gated Ca 2؉ channels (VGCC) play an important role in dendritic development, neuronal survival, and synaptic plasticity. Recent studies have demonstrated that the gonadal steroid estrogen rapidly induces Ca 2؉ influx in hippocampal neurons, which is required for neuroprotection and potentiation of LTP. The mechanism by which estrogen rapidly induces this Ca 2؉ influx is not clearly understood. We show by electrophysiological studies that extremely low concentrations of estrogens acutely potentiate VGCC in hippocampal neurons, hippocampal slices, and HEK-293 cells transfected with neuronal L-type VGCC, in a manner that was estrogen receptor (ER)-independent. Equilibrium, competitive, and whole-cell binding assays indicate that estrogen directly interacts with the VGCC. Furthermore, a L-type VGCC antagonist to the dihydropyridine site displaced estrogen binding to neuronal membranes, and the effects of estrogen were markedly attenuated in a mutant, dihydropyridineinsensitive L-type VGCC, demonstrating a direct interaction of estrogens with L-type VGCC. Thus, estrogen-induced potentiation of calcium influx via L-type VGCC may link electrical events with rapid intracellular signaling seen with estrogen exposure leading to modulation of synaptic plasticity, neuroprotection, and memory formation.estrogen receptors ͉ signaling ͉ estradiol ͉ memory A large body of evidence shows that estrogens exert multiple rapid effects on the structure and function of neurons in a variety of brain regions, including the hippocampus (1). For example, estrogens rapidly potentiate kainite-induced currents in hippocampal neurons from wild-type (2) as well as from estrogenreceptor (ER)-␣ knockout (3) mice and induce rapid spine synapse formation in the CA1 hippocampus of ovariectomized (OVX) rats (4). Furthermore, acute application of estrogens to hippocampal slices increases NMDA and AMPA receptor transmission (5), induces long-term potentiation (LTP) and long-term depression (LTD) (6), and rapidly modulates neuronal excitability in rat medial amygdala (7) and hippocampus(8).It is well known that estrogens interact with cell membrane components and initiate signaling events leading to a rise in intracellular Ca 2ϩ , and activation of Src kinase, G protein-coupled receptor (GPCR), MAPK, PI3K/AKT, PKA, and adenylyl cyclase (9). The mechanism(s) by which estrogens induce these rapid and diverse effects remains largely unknown. Ca 2ϩ is a second messenger that can trigger the modification of synaptic efficacy. A plasticity-induction protocol like repetitive low-frequency synaptic stimulation (10) induces the elevation of postsynaptic intracellular Ca 2ϩ . The level of intracellular Ca 2ϩ concentration can activate numerous kinases like CAMK, PKA, PKC, MAPK, PI3K, or phosphatases (11-15), which, respectively, phosphorylate or dephosphorylate ion channels, transcription factors, and other proteins that are involved in synaptic plasticity and memory formation. Because voltage-gated Ca 2ϩ channels (VGCC)-mediated extracellular Ca ...

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“…The results of the present study indicate that neonatal estradiol exposure significantly downregulates synaptogenesis related genes such as NMDAR 2B, NETRIN-1, BDNF, MT5-MMP and TNF-α in female rat POA compared to control rats as seen during adulthood. One of the differentially expressed gene, namely, NMDA2B is a subunit of NMDA receptor and NMDA receptors are known to have an important role in learning and memory, as well as the formation of excitatory synapses and the synaptic transmission [1]. The other down-regulated genes, Netrin-1 is a novel regulator of synaptogenesis and synaptic function [30,34], MT5-MMP an enzyme known to have a function in synapse remodeling [22] and Tumor necrosis factor-α (TNF-α) [24,30], have been identified as neurotrophic factors which regulate synaptogenesis, synaptic transmission, and plasticity.…”

Section: Brain Regions Preoptic Area Hypothalamus Pituitarymentioning

confidence: 99%

Neonatal exposure to 17β-estradiol down-regulates the expression of synaptogenesis related genes in selected brain regions of adult female rats

et al. 2015

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Aims: Administration of estradiol or compounds with estrogenic activity to newborn female rats results in irreversible masculinization as well as defeminization in the brain and the animals exhibit altered reproductive behavior as adults. The cellular and molecular mechanism involved in inducing the irreversible changes is largely unknown. In the present study, we have monitored the changes in the expression of selected synaptogenesis related genes in the sexually dimorphic brain regions such as POA, hypothalamus and pituitary following 17β-estradiol administration to neonatal female rats. Main methods: Female Wistar rats which were administered 17β-estradiol on day 2 and 3 after birth were sacrificed 120 days later and the expression levels of genes implicated in synaptogenesis were monitored by semi-quantitative reverse transcription PCR. Since estradiol induced up-regulation of COX-2 in POA is a marker for estradiol induced masculinization as well as defeminization, in the present study only animals in which the increase in expression of COX-2 gene was observed in POA were included in the study. Key findings: Down-regulation of genes such as NMDA-2B, NETRIN-1, BDNF, MT-5 MMP and TNF-α was observed in the pre-optic area of neonatally E2 treated female rat brain but not in hypothalamus and pituitary compared to the vehicle-treated controls as assessed by RT-PCR and Western blot analysis. Significance: Our results suggest a possibility that down-regulation of genes associated with synaptogenesis in POA, may be resulting in disruption of the cyclical regulation of hormone secretion by pituitary the consequence of which could be infertility and altered reproductive behavior.

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Estrogen modulates synaptic N‐methyl‐D‐aspartate receptor subunit distribution in the aged hippocampus

Cited by 127 publications

References 41 publications

Nongenomic Actions of 17-β Estradiol Restore Respiratory Neuroplasticity in Young Ovariectomized Female Rats

Nongenomic Actions of 17-β Estradiol Restore Respiratory Neuroplasticity in Young Ovariectomized Female Rats

Estrogens directly potentiate neuronal L-type Ca ²⁺ channels

Neonatal exposure to 17β-estradiol down-regulates the expression of synaptogenesis related genes in selected brain regions of adult female rats

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Estrogen modulates synaptic N‐methyl‐D‐aspartate receptor subunit distribution in the aged hippocampus

Cited by 127 publications

References 41 publications

Nongenomic Actions of 17-β Estradiol Restore Respiratory Neuroplasticity in Young Ovariectomized Female Rats

Nongenomic Actions of 17-β Estradiol Restore Respiratory Neuroplasticity in Young Ovariectomized Female Rats

Estrogens directly potentiate neuronal L-type Ca 2+ channels

Neonatal exposure to 17β-estradiol down-regulates the expression of synaptogenesis related genes in selected brain regions of adult female rats

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Estrogens directly potentiate neuronal L-type Ca ²⁺ channels