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The ketamine metabolite (\n                      <jats:italic>2R,6R<\/jats:italic>\n                      )\u2010hydroxynorketamine (HNK) has been shown to modulate protein synthesis, but its effects on memory in AD models remain elusive.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>We investigated the effects of HNK on hippocampal protein synthesis, long\u2010term potentiation (LTP), and memory in AD mouse models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>HNK activated extracellular signal\u2010regulated kinase 1\/2 (ERK1\/2), mechanistic target of rapamycin (mTOR), and p70S6 kinase 1 (S6K1)\/ribosomal protein S6 signaling pathways. Treatment with HNK rescued hippocampal LTP and memory deficits in amyloid\u2010\u03b2 oligomers (A\u03b2O)\u2010infused mice in an ERK1\/2\u2010dependent manner. Treatment with HNK further corrected aberrant transcription, LTP and memory in aged APP\/PS1 mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>Our findings demonstrate that HNK induces signaling and transcriptional responses that correct synaptic and memory deficits in AD mice. These results raise the prospect that HNK could serve as a therapeutic approach in AD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>The ketamine metabolite HNK activates hippocampal ERK\/mTOR\/S6 signaling pathways.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>HNK corrects hippocampal synaptic and memory defects in two mouse models of AD.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Rescue of synaptic and memory impairments by HNK depends on ERK signaling.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>HNK corrects aberrant transcriptional signatures in APP\/PS1 mice.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.14034","type":"journal-article","created":{"date-parts":[[2024,6,27]],"date-time":"2024-06-27T04:45:37Z","timestamp":1719463537000},"page":"5398-5410","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["The ketamine metabolite (\n                    <i>2R,6R<\/i>\n                    )\u2010hydroxynorketamine rescues hippocampal mRNA translation, synaptic plasticity and memory in mouse models of Alzheimer's disease"],"prefix":"10.1002","volume":"20","author":[{"given":"Felipe C.","family":"Ribeiro","sequence":"first","affiliation":[{"name":"Institute of Medical Biochemistry Leopoldo de Meis Federal University of Rio de Janeiro Rio de Janeiro Rio de Janeiro 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Rio de Janeiro Rio de Janeiro Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mychael V.","family":"Lourenco","sequence":"additional","affiliation":[{"name":"Institute of Medical Biochemistry Leopoldo de Meis Federal University of Rio de Janeiro Rio de Janeiro Rio de Janeiro Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ottavio","family":"Arancio","sequence":"additional","affiliation":[{"name":"Taub Institute for Research on Alzheimer's Disease and the Aging Brain Columbia University New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Argel","family":"Aguilar\u2010Valles","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Carleton University  Ottawa Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nahum","family":"Sonenberg","sequence":"additional","affiliation":[{"name":"Department of Biochemistry McGill University  Montreal Quebec 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