Membrane-associated estrogen receptor α prevents the amyloid β-induced suppression of GIRK channel activity in hippocampal neurons from female mice

TL;DR

Estrogen protects female mouse brain cells from a harmful protein linked to Alzheimer's, which may explain why women are more likely to develop the disease.

Contribution

The study identifies membrane-associated estrogen receptor α as a sex-specific resilience factor against amyloid β-induced suppression of GIRK channels in female hippocampal neurons.

Findings

Local estrogen production in female hippocampal neurons protects GIRK channel activity from suppression by oligomeric amyloid β.

Resilience to oAβ suppression in female neurons requires membrane-associated estrogen receptor α and caveolin-1.

Blocking estrogen receptor α in females unmasked the same suppression mechanism previously observed in male neurons.

Abstract

Amyloid β oligomers (oAβ) are a key pathogenic driver in Alzheimer’s Disease (AD). Neuronal G protein-gated inwardly rectifying K+ (GIRK/Kir3) channels are important regulators of neuronal excitability and prominent somatodendritic effectors for inhibitory G protein-coupled receptors, including the γ-aminobutyric acid type B receptor (GABABR). We previously reported a male-specific suppression of GIRK channel activity in hippocampal (HPC) neurons evoked by oAβ in in vitro, ex vivo, and in vivo mouse models of AD, and showed that this adaptation correlated with synaptic and cognitive impairment. Using pharmacological approaches, we showed that this adaptation is mediated by co-activation of cellular prion protein (PrPC) and metabotropic glutamate receptor 5 (mGluR5) and requires activation of cytosolic phospholipase A2 α (cPLA2α). However, the mechanisms underlying the sex specificity was unknown. Given the clinical context that females exhibit a 2-fold higher incidence of AD than males, and the loss of neuroprotective estrogen by menopause contributes to the sex differences in AD, we postulated that estrogen-associated resilience underlies this sex dimorphism of oAβ action.

To examine the strength of GIRK-dependent signaling in HPC neurons, we performed electrophysiology in primary HPC cultures from neonatal male and female mice and then measured whole-cell currents evoked by the direct-acting GIRK channel agonist ML297 and the GABABR-selective agonist baclofen. We used an array of genetic and pharmacological approaches to investigate the molecular mechanism(s) underlying the vulnerability and resilience of GIRK channel activity to oAβ in male and female HPC neurons, respectively.

We found that resilience to the oAβ-induced and PrPC/mGluR5-dependent suppression of GIRK channel activity in female HPC neurons is conferred by membrane-associated estrogen receptor α (mERα) and caveolin 1 (Cav1). When this resilience factor is blocked or absent, oAβ suppresses GIRK channel activity in female HPC neurons via the same PrPC-mGluR5-cPLA2α signaling pathway identified previously in male neurons.

As estrogen levels decline with aging and menopause, the protective influence of mERα/Cav1 may diminish, unmasking the oAβ-induced suppression of GIRK channel activity and exacerbating disease progression in females.

While amyloid β plaques (Aβ) are notable hallmarks of Alzheimer’s Disease (AD), cognitive impairment in the early stages of the disease tracks more closely with the level of soluble Aβ oligomers (oAβ) in the brain. oAβ promotes cognitive deficits by disrupting the balance of excitatory and inhibitory influences on neurons in brain regions important for learning and memory such as the hippocampus, but the underlying molecular targets of oAβ and its pathogenic mechanisms are not fully understood. We recently demonstrated that oAβ weakens the activity of a prominent inhibitory influence on neuronal excitability (the GIRK channel) in the hippocampus of male but not female mice. This sexually dimorphic effect of oAβ was interesting and unexpected given that women are twice as likely to develop AD than men, and because disease progression is more aggressive in women. In this study, we investigated the mechanisms underlying the resilience of GIRK channels in female hippocampal neurons to oAβ. We found that resilience is conferred by estrogen and one of its receptors. When the influence of this receptor is diminished using pharmacological or genetic interventions, oAβ weakens GIRK channel activity in female and male neurons to a similar degree, and via the same mechanism. We speculate that with the onset of menopause, the protective influence of estrogen on GIRK channel activity in the hippocampus begins to wane. This, combined with other female-specific effects of oAβ on neuronal activity, contributes to the increased incidence and severity of AD in females.

The online version contains supplementary material available at 10.1186/s13293-025-00776-7.

In hippocampal (HPC) neurons from female mice, local estrogen production protects GIRK channel activity from suppression by oligomeric amyloid β (oAβ).Inhibition of estrogen receptor α (ERα), but not estrogen receptor β (ERβ) or G protein-coupled estrogen receptor (GPER), unmasked the oAβ-induced suppression of GIRK channel activity in female HPC neurons.Without ERα protection, oAβ suppressed GIRK channel activity in female HPC neurons through the same mechanism identified previously in male HPC neurons involving cellular prion protein (PrPC), metabotropic glutamate receptor 5 (mGluR5), and cytosolic phospholipase A2α (cPLA2α).mGluR5-associated regulation of GIRK channel plasticity is blocked in female HPC neurons independent of oAβ. Resilience of GIRK channel activity in female HPC neurons to mGluR5 agonist and oAβ requires membrane-associated ERα (mERα) and caveolin-1 (Cav1).

In hippocampal (HPC) neurons from female mice, local estrogen production protects GIRK channel activity from suppression by oligomeric amyloid β (oAβ).

Inhibition of estrogen receptor α (ERα), but not estrogen receptor β (ERβ) or G protein-coupled estrogen receptor (GPER), unmasked the oAβ-induced suppression of GIRK channel activity in female HPC neurons.

Without ERα protection, oAβ suppressed GIRK channel activity in female HPC neurons through the same mechanism identified previously in male HPC neurons involving cellular prion protein (PrPC), metabotropic glutamate receptor 5 (mGluR5), and cytosolic phospholipase A2α (cPLA2α).

mGluR5-associated regulation of GIRK channel plasticity is blocked in female HPC neurons independent of oAβ.

Resilience of GIRK channel activity in female HPC neurons to mGluR5 agonist and oAβ requires membrane-associated ERα (mERα) and caveolin-1 (Cav1).

The online version contains supplementary material available at 10.1186/s13293-025-00776-7.

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