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Two Akt isoforms, Akt1 and Akt3, are highly expressed in hippocampal pyramidal cells. We explored the roles of Akt1 and Akt3, respectively, in spatial cognition and underlying mechanisms.<\/jats:p><\/jats:sec>Methods<\/jats:title>We used Akt1<\/jats:italic> knockout (Akt1<\/jats:italic>\u2010KO<\/jats:styled-content>) and Akt3<\/jats:italic> knockout (Akt3<\/jats:italic>\u2010KO<\/jats:styled-content>) mice to examine the influence of Akt1<\/jats:italic> and Akt3<\/jats:italic> deficiency on spatial memory, as well as induction and maintenance of hippocampal CA<\/jats:styled-content>1 NMDA<\/jats:styled-content> receptor\u2010dependent and protein synthesis\u2010dependent long\u2010term potentiation (LTP<\/jats:styled-content>).<\/jats:p><\/jats:sec>Results<\/jats:title>Long\u2010term spatial memory was impaired in Akt3<\/jats:italic>\u2010KO<\/jats:styled-content> mice, but not in Akt1<\/jats:italic>\u2010KO<\/jats:styled-content> mice, as assessed by the Morris water maze task. Akt3<\/jats:italic>\u2010KO<\/jats:styled-content> and Akt1<\/jats:italic>\u2010KO<\/jats:styled-content> mice displayed reductions in brain size without concurrent changes in the number of pyramidal cells or basal properties of synaptic transmission. One\u2010train high\u2010frequency stimulation (HFS<\/jats:styled-content> \u00d7 1) induced NMDA<\/jats:styled-content> receptor\u2010dependent LTP<\/jats:styled-content> in Akt3<\/jats:italic>\u2010KO<\/jats:styled-content> mice and Akt1<\/jats:italic>\u2010KO<\/jats:styled-content> mice. Four\u2010train HFS<\/jats:styled-content> (HFS<\/jats:styled-content> \u00d7 4) induced rapamycin\u2010sensitive long\u2010<\/jats:bold><\/jats:italic>LTP<\/jats:styled-content> in Akt1<\/jats:italic>\u2010KO<\/jats:styled-content> mice, but not Akt3<\/jats:italic>\u2010KO<\/jats:styled-content> mice. Basal level of mTOR<\/jats:styled-content> phosphorylation was reduced in Akt3<\/jats:italic>\u2010KO<\/jats:styled-content> mice rather than Akt1<\/jats:italic>\u2010KO<\/jats:styled-content> mice. HFS<\/jats:styled-content> \u00d7 4 induced an elevation of mTOR<\/jats:styled-content> and p70S6K phosphorylation in Akt1<\/jats:italic>\u2010KO<\/jats:styled-content> mice, which led to enhanced 4EBP<\/jats:styled-content>2 and eIF<\/jats:styled-content>4E phosphorylation along with an increase in AMPA<\/jats:styled-content> receptor protein. However, the same protocol of HFS<\/jats:styled-content> \u00d7 4 failed to trigger the mTOR<\/jats:styled-content>\u2010p70S6K signalling cascade or increase 4EBP<\/jats:styled-content>2 and eIF<\/jats:styled-content>4E phosphorylation in Akt3<\/jats:italic>\u2010KO mice.<\/jats:p><\/jats:sec>Conclusion<\/jats:title>The Akt3<\/jats:italic> deficiency via<\/jats:italic> inactivation of mTOR<\/jats:styled-content> suppresses HFS<\/jats:styled-content> \u00d7 4\u2010induced mTOR<\/jats:styled-content>\u2010p70S6K signalling to reduce phosphorylation of 4EBP<\/jats:styled-content> and eIF<\/jats:styled-content>4E, which impairs protein synthesis\u2010dependent long\u2010LTP<\/jats:styled-content> and long\u2010term spatial cognitive function.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apha.13167","type":"journal-article","created":{"date-parts":[[2018,7,27]],"date-time":"2018-07-27T16:43:28Z","timestamp":1532709808000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Akt3 deletion in mice impairs spatial cognition and hippocampal CA<\/scp>1 long long\u2010term potentiation through downregulation of mTOR<\/scp>"],"prefix":"10.1111","volume":"225","author":[{"given":"Tingting","family":"Zhang","sequence":"first","affiliation":[{"name":"State Key Lab of Reproductive Medicine Nanjing Medical University Nanjing China"},{"name":"Department of Physiology Nanjing Medical University Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaochun","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Neurology First Affiliated Hospital of Nanjing Medical University Nanjing 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