The role of hippocampal estradiol in synaptic plasticity and memory: A systematic review

Finney, Caitlin A.; Shvetcov, Artur; Westbrook, R. Frederick; Jones, Nicole M.; Morris, Margaret J.

doi:10.1016/j.yfrne.2019.100818

Cited by 30 publications

(16 citation statements)

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“…Further, there is some evidence that the lesser studied ERs, including the G protein-coupled ER (GPER), may play a role in neuroprotection as well (Bai et al, 2020; Han et al, 2019; Herrera et al, 2011; Tang et al, 2014). It is likely that, similar to what has been found in hippocampal-dependent memory, combined ER activity is needed to facilitate the pro-estrogenic effects of estrogen and estrogenic compounds like tamoxifen (Finney et al, 2020c).…”

Section: Discussionmentioning

confidence: 98%

The selective estrogen receptor modulator tamoxifen protects against subtle cognitive decline and early markers of injury twenty-four hours after hippocampal silent infarct

Finney

Shvetcov

Westbrook

et al. 2020

Preprint

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Silent infarcts (SI) are subcortical cerebral infarcts that occur in the absence of typical symptoms associated with ischemia but are linked to cognitive decline and the development of dementia. There are no approved treatments for SI, but one potential treatment is tamoxifen, a selective estrogen receptor modulator. While SI can have long-term consequences, it is critical to establish whether treatments are able to selectively target its early consequences, to avoid progression to complete injury. We induced SI in the dorsal hippocampal CA1 of rats and assessed whether tamoxifen is protective 24 hours later against cognitive deficits and injury responses to SI including gliosis, apoptosis, inflammation and changes in estrogen receptors (ERs). Hippocampal SI led to subtle cognitive impairment on the object place recognition task, an effect ameliorated by tamoxifen administration. SI did not lead to detectable hippocampal cell loss but did increase apoptosis, astrogliosis, microgliosis and inflammation. Tamoxifen protected against the effects of SI on all measures except microgliosis. SI also increased ERα and decreased ERβ in the hippocampus, which was again mitigated by tamoxifen. Exploratory data analyses using scatterplot matrices and principal component analysis indicated that the SI rats given tamoxifen were indistinguishable from sham controls. Further, SI rats were significantly different from all other groups, an effect produced by low levels of ERα and increased apoptosis, gliosis, inflammation, ERβ, and time spent with the unmoved object. The results demonstrate that tamoxifen is protective against the early cellular and cognitive consequences of hippocampal SI as early as 24 hours after injury. This effect is driven by mitigation of apoptosis, gliosis, and inflammation and normalization of ER levels in the CA1, leading to improved cognitive outcomes after hippocampal SI.

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Section: Discussionmentioning

confidence: 98%

The selective estrogen receptor modulator tamoxifen protects against subtle cognitive decline and early markers of injury twenty-four hours after hippocampal silent infarct

Finney

Shvetcov

Westbrook

et al. 2020

Preprint

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“…The entorhinal cortex is tightly interconnected with both the neocortex and hippocampal formation, and the effects of estrogens and progesterone on synaptic transmission in the entorhinal cortex are likely to contribute to cognitive processes through multiple intracellular cellular signaling mechanisms (Burwell, 2000;Finney et al, 2020;Witter et al, 2017). Estrogens and progesterone have genomic effects on synaptic function that are expressed over hours to days (J.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the potentiation of fEPSP amplitude observed here may be due to a GPER1-mediated reduction in synaptic inhibition in the entorhinal cortex, which could be expressed without a change in the paired-pulse ratio. The rapid potentiation of fEPSP amplitude in the entorhinal cortex induced by E2 may be initiated by the activation of the G protein α-subunit by GPER1 and resulting modulation of adenylyl cyclase and cAMP signaling (Alexander et al, 2017;Finney et al, 2020;Lu & Herndon, 2017). The activation of GPER1 can also lead to the activation of epidermal growth factor receptor (EGFR) and stimulation of ERK.…”

Section: Gper1 Signaling Mechanismsmentioning

confidence: 99%

“…Variations in circulating estrogen levels are able to improve cognitive performance and modulate shifts in the use of learning and memory strategies (Finney et al, 2020;Hamson et al, 2016;Hussain et al, 2014). Women taking oral contraceptives exhibit improvements in verbal memory during the active phase of their regimen, when estrogens are elevated (Mordecai et al, 2008).…”

mentioning

confidence: 99%

“…Estrogens can facilitate excitatory synaptic transmission in the CA1 region by increasing dendritic spine density and can also induce rapid increases in excitatory synaptic strength (Finney et al, 2020;Sellers et al, 2015b). Hippocampal spine densities vary with the estrous cycle and are greatest during proestrus when the levels of estrogens and progesterone are high (Woolley et al, 1990), and the decline in dendritic spine density that occurs following ovariectomy can be prevented by estrogen replacement (Gould et al, 1990;Woolley & McEwen, 1993).…”

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confidence: 99%

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G protein‐coupled estrogen receptor‐1 enhances excitatory synaptic responses in the entorhinal cortex

et al. 2021

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Activation of estrogen receptors is thought to modulate cognitive function in the hippocampus, prefrontal cortex, and striatum by affecting both excitatory and inhibitory synaptic transmission. The entorhinal cortex is a major source of cortical sensory and associational input to the hippocampus, but it is unclear whether either estrogens or progestogens may modulate cognitive function through effects on synaptic transmission in the entorhinal cortex. This study assessed the effects of the brief application of either 17-β estradiol (E2) or progesterone on excitatory glutamatergic synaptic transmission in the female rat entorhinal cortex in vitro. Rats were ovariectomized on postnatal day (PD) 63 and also received subdermal E2 implants to maintain constant low levels of circulating E2 on par with estrus. Electrophysiological recordings from brain slices were obtained between PD70 and PD86, and field excitatory postsynaptic potentials (fEPSPs) reflecting the activation of the superficial layers of the entorhinal cortex were evoked by the stimulation of layer I afferents.The application of E2 (10 nM) for 20 min resulted in a small increase in the amplitude of fEPSPs that reversed during the 30-min washout period. The application of the ERα agonist propylpyrazoletriol (PPT) (100 nM) or the β agonist DPN (1 μM) did not significantly affect synaptic responses. However, the application of the G proteincoupled estrogen receptor-1 (GPER1) agonist G1 (100 nM) induced a reversible increase in fEPSP amplitude similar to that induced by E2. Furthermore, the potentiation of responses induced by G1 was blocked by the GPER1 antagonist G15 (1 μM).

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17β‐Estradiol reduces inhibitory synaptic currents in entorhinal cortex neurons through G protein‐coupled estrogen receptor‐1 activation of extracellular signal‐regulated kinase

Batallán Burrowes,

Moisan,

Garrone

et al. 2024

Hippocampus

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Estrogens are believed to modulate cognitive functions in part through the modulation of synaptic transmission in the cortex and hippocampus. Administration of 17β‐estradiol (E2) can rapidly enhance excitatory synaptic transmission in the hippocampus and facilitate excitatory synaptic transmission in rat lateral entorhinal cortex via activation of the G protein‐coupled estrogen receptor‐1 (GPER1). To assess the mechanisms through which GPER1 activation facilitates synaptic transmission, we assessed the effects of acute 10 nM E2 administration on pharmacologically isolated evoked excitatory and inhibitory synaptic currents in layer II/III entorhinal neurons. Female Long‐Evans rats were ovariectomized between postnatal day (PD) 63 and 74 and implanted with a subdermal E2 capsule to maintain continuous low levels of E2. Electrophysiological recordings were obtained between 7 and 20 days after ovariectomy. Application of E2 for 20 min did not significantly affect AMPA or NMDA receptor‐mediated excitatory synaptic currents. However, GABA receptor‐mediated inhibitory synaptic currents (IPSCs) were markedly reduced by E2 and returned towards baseline levels during the 20‐min washout period. The inhibition of GABA‐mediated IPSCs was blocked in the presence of the GPER1 receptor antagonist G15. GPER1 can modulate protein kinase A (PKA), but blocking PKA with intracellular KT5720 did not prevent the E2‐induced reduction in IPSCs. GPER1 can also stimulate extracellular signal‐regulated kinase (ERK), a negative modulator of GABAA receptors, and blocking activation of ERK with PD90859 prevented the E2‐induced reduction of IPSCs. E2 can therefore result in a rapid GPER1 and ERK signaling‐mediated reduction in GABA‐mediated IPSCs. This provides a novel mechanism through which E2 can rapidly modulate synaptic excitability in entorhinal layer II/III neurons and may also contribute to E2 and ERK‐dependent alterations in synaptic transmission in other brain areas.

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The role of hippocampal estradiol in synaptic plasticity and memory: A systematic review

Cited by 30 publications

References 100 publications

The selective estrogen receptor modulator tamoxifen protects against subtle cognitive decline and early markers of injury twenty-four hours after hippocampal silent infarct

The selective estrogen receptor modulator tamoxifen protects against subtle cognitive decline and early markers of injury twenty-four hours after hippocampal silent infarct

G protein‐coupled estrogen receptor‐1 enhances excitatory synaptic responses in the entorhinal cortex

17β‐Estradiol reduces inhibitory synaptic currents in entorhinal cortex neurons through G protein‐coupled estrogen receptor‐1 activation of extracellular signal‐regulated kinase

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