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Neuronal G protein-gated inwardly rectifying K\n                      <jats:sup>+<\/jats:sup>\n                      (GIRK\/Kir3) channels are important regulators of neuronal excitability and prominent somatodendritic effectors for inhibitory G protein-coupled receptors, including the \u03b3-aminobutyric acid type B receptor (GABA\n                      <jats:sub>B<\/jats:sub>\n                      R). We previously reported a male-specific suppression of GIRK channel activity in hippocampal (HPC) neurons evoked by oA\u03b2 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 (PrP\n                      <jats:sup>C<\/jats:sup>\n                      ) and metabotropic glutamate receptor 5 (mGluR5) and requires activation of cytosolic phospholipase A2 \u03b1 (cPLA\n                      <jats:sub>2<\/jats:sub>\n                      \u03b1). 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 oA\u03b2 action.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      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 GABA\n                      <jats:sub>B<\/jats:sub>\n                      R-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 oA\u03b2 in male and female HPC neurons, respectively.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We found that resilience to the oA\u03b2-induced and PrP\n                      <jats:sup>C<\/jats:sup>\n                      \/mGluR5-dependent suppression of GIRK channel activity in female HPC neurons is conferred by membrane-associated estrogen receptor \u03b1 (mER\u03b1) and caveolin 1 (Cav1). When this resilience factor is blocked or absent, oA\u03b2 suppresses GIRK channel activity in female HPC neurons via the same PrP\n                      <jats:sup>C<\/jats:sup>\n                      -mGluR5-cPLA\n                      <jats:sub>2<\/jats:sub>\n                      \u03b1 signaling pathway identified previously in male neurons.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>As estrogen levels decline with aging and menopause, the protective influence of mER\u03b1\/Cav1 may diminish, unmasking the oA\u03b2-induced suppression of GIRK channel activity and exacerbating disease progression in females.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Plain english summary<\/jats:title>\n                    <jats:p>While amyloid \u03b2 plaques (A\u03b2) are notable hallmarks of Alzheimer\u2019s Disease (AD), cognitive impairment in the early stages of the disease tracks more closely with the level of soluble A\u03b2 oligomers (oA\u03b2) in the brain. oA\u03b2 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 oA\u03b2 and its pathogenic mechanisms are not fully understood. We recently demonstrated that oA\u03b2 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 oA\u03b2 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 oA\u03b2. 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, oA\u03b2 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 oA\u03b2 on neuronal activity, contributes to the increased incidence and severity of AD in females.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13293-025-00776-7","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T14:43:24Z","timestamp":1762440204000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Membrane-associated estrogen receptor \u03b1 prevents the amyloid \u03b2-induced suppression of GIRK channel activity in hippocampal neurons from female mice"],"prefix":"10.1186","volume":"16","author":[{"given":"Haichang","family":"Luo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ezequiel","family":"Marron Fernandez de Velasco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaeyoon","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Praseuth","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Mermelstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph V.","family":"Bonventre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul S.","family":"Cooke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Wickman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,6]]},"reference":[{"issue":"1","key":"776_CR1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-021-00269-y","volume":"7","author":"DS Knopman","year":"2021","unstructured":"Knopman DS, Amieva H, Petersen RC, Chetelat G, Holtzman DM, Hyman BT, et al. 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