{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T13:10:47Z","timestamp":1790428247951,"version":"4.1.0"},"reference-count":112,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"856","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Signal."],"published-print":{"date-parts":[[2024,10]]},"abstract":"<jats:p>\n                    Alzheimer\u2019s disease (AD) is a progressive neurodegenerative disease characterized by amyloid plaques and cognitive decline, the latter of which is thought to be driven by soluble oligomeric amyloid-\u03b2 (oA\u03b2). The dysregulation of G protein\u2013gated inwardly rectifying K\n                    <jats:sup>+<\/jats:sup>\n                    (GIRK; also known as Kir3) channels has been implicated in rodent models of AD. Here, seeking mechanistic insights, we uncovered a sex-dependent facet of GIRK-dependent signaling in AD-related amyloid pathophysiology. Synthetic oA\u03b2\n                    <jats:sub>1\u201342<\/jats:sub>\n                    suppressed GIRK-dependent signaling in hippocampal neurons from male mice, but not from female mice. This effect required cellular prion protein, the receptor mGluR5, and production of arachidonic acid by the phospholipase PLA\n                    <jats:sub>2<\/jats:sub>\n                    . Although oA\u03b2 suppressed GIRK channel activity only in male hippocampal neurons, intrahippocampal infusion of oA\u03b2 or genetic suppression of GIRK channel activity in hippocampal pyramidal neurons impaired performance on a memory test in both male and female mice. Moreover, genetic enhancement of GIRK channel activity in hippocampal pyramidal neurons blocked oA\u03b2-induced cognitive impairment in both male and female mice. In APP\/PS1 AD model mice, GIRK-dependent signaling was diminished in hippocampal CA1 pyramidal neurons from only male mice before cognitive deficit was detected. However, enhancing GIRK channel activity rescued cognitive deficits in older APP\/PS1 mice of both sexes. Thus, whereas diminished GIRK channel activity contributes to cognitive deficits in male mice with increased oA\u03b2 burden, enhancing its activity may have therapeutic potential for both sexes.\n                  <\/jats:p>","DOI":"10.1126\/scisignal.ado4132","type":"journal-article","created":{"date-parts":[[2024,10,1]],"date-time":"2024-10-01T13:58:52Z","timestamp":1727791132000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":13,"title":["Amyloid-\u03b2 oligomers trigger sex-dependent inhibition of GIRK channel activity in hippocampal neurons in mice"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5120-9232","authenticated-orcid":true,"given":"Haichang","family":"Luo","sequence":"first","affiliation":[{"name":"Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ezequiel","family":"Marron Fernandez","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7506-8972","authenticated-orcid":true,"given":"Benjamin","family":"Gansemer","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"McKinzie","family":"Frederick","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0265-8124","authenticated-orcid":true,"given":"Carolina","family":"Aguado","sequence":"additional","affiliation":[{"name":"Synaptic Structure Laboratory, Departmento de Ciencias M\u00e9dicas, Instituto de Biomedicina, Facultad de Medicina, Universidad de Castilla\u2013La Mancha, Campus Biosanitario, Albacete 02006, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2001-9545","authenticated-orcid":true,"given":"Rafael","family":"Luj\u00e1n","sequence":"additional","affiliation":[{"name":"Synaptic Structure Laboratory, Departmento de Ciencias M\u00e9dicas, Instituto de Biomedicina, Facultad de Medicina, Universidad de Castilla\u2013La Mancha, Campus Biosanitario, Albacete 02006, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0856-6522","authenticated-orcid":true,"given":"Stanley A.","family":"Thayer","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5179-9540","authenticated-orcid":true,"given":"Kevin","family":"Wickman","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)32205-4"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/bies.201500004"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-022-02024-7"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/hbm.20708"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awv007"},{"key":"e_1_3_2_7_2","first-page":"38","article-title":"Selective alterations of neurons and circuits related to early memory loss in Alzheimer\u2019s disease","volume":"8","author":"Llorens-Martin M.","year":"2014","unstructured":"M. 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