Tingting Zhang1,2, Zhaochun Shi3, Ya Wang2, Ling Wang2, Baofeng Zhang2, Guiquan Chen4, Qi Wan3, Ling Chen1,2. 1. State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, China. 2. Department of Physiology, Nanjing Medical University, Nanjing, China. 3. Department of Neurology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China. 4. State Key Laboratory of Pharmaceutical Biotechnology, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China.
Abstract
AIM: Loss-of-function mutation of Akt3 in humans has been associated with microcephaly and cognitive defects. 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. METHODS: We used Akt1 knockout (Akt1-KO) and Akt3 knockout (Akt3-KO) mice to examine the influence of Akt1 and Akt3 deficiency on spatial memory, as well as induction and maintenance of hippocampal CA1 NMDA receptor-dependent and protein synthesis-dependent long-term potentiation (LTP). RESULTS: Long-term spatial memory was impaired in Akt3-KO mice, but not in Akt1-KO mice, as assessed by the Morris water maze task. Akt3-KO and Akt1-KO mice displayed reductions in brain size without concurrent changes in the number of pyramidal cells or basal properties of synaptic transmission. One-train high-frequency stimulation (HFS × 1) induced NMDA receptor-dependent LTP in Akt3-KO mice and Akt1-KO mice. Four-train HFS (HFS × 4) induced rapamycin-sensitive long-LTP in Akt1-KO mice, but not Akt3-KO mice. Basal level of mTOR phosphorylation was reduced in Akt3-KO mice rather than Akt1-KO mice. HFS × 4 induced an elevation of mTOR and p70S6K phosphorylation in Akt1-KO mice, which led to enhanced 4EBP2 and eIF4E phosphorylation along with an increase in AMPA receptor protein. However, the same protocol of HFS × 4 failed to trigger the mTOR-p70S6K signalling cascade or increase 4EBP2 and eIF4E phosphorylation in Akt3-KO mice. CONCLUSION: The Akt3 deficiency via inactivation of mTOR suppresses HFS × 4-induced mTOR-p70S6K signalling to reduce phosphorylation of 4EBP and eIF4E, which impairs protein synthesis-dependent long-LTP and long-term spatial cognitive function.
AIM: Loss-of-function mutation of Akt3 in humans has been associated with microcephaly and cognitive defects. 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. METHODS: We used Akt1 knockout (Akt1-KO) and Akt3 knockout (Akt3-KO) mice to examine the influence of Akt1 and Akt3deficiency on spatial memory, as well as induction and maintenance of hippocampal CA1 NMDA receptor-dependent and protein synthesis-dependent long-term potentiation (LTP). RESULTS: Long-term spatial memory was impaired in Akt3-KO mice, but not in Akt1-KO mice, as assessed by the Morris water maze task. Akt3-KO and Akt1-KO mice displayed reductions in brain size without concurrent changes in the number of pyramidal cells or basal properties of synaptic transmission. One-train high-frequency stimulation (HFS × 1) induced NMDA receptor-dependent LTP in Akt3-KO mice and Akt1-KO mice. Four-train HFS (HFS × 4) induced rapamycin-sensitive long-LTP in Akt1-KO mice, but not Akt3-KO mice. Basal level of mTOR phosphorylation was reduced in Akt3-KO mice rather than Akt1-KO mice. HFS × 4 induced an elevation of mTOR and p70S6K phosphorylation in Akt1-KO mice, which led to enhanced 4EBP2 and eIF4E phosphorylation along with an increase in AMPA receptor protein. However, the same protocol of HFS × 4 failed to trigger the mTOR-p70S6K signalling cascade or increase 4EBP2 and eIF4E phosphorylation in Akt3-KO mice. CONCLUSION: The Akt3 deficiency via inactivation of mTOR suppresses HFS × 4-induced mTOR-p70S6K signalling to reduce phosphorylation of 4EBP and eIF4E, which impairs protein synthesis-dependent long-LTP and long-term spatial cognitive function.
Authors: Tarak Srivastava; Trupti Joshi; Yuexu Jiang; Daniel P Heruth; Mohamed H Rezaiekhaligh; Jan Novak; Vincent S Staggs; Uri S Alon; Robert E Garola; Ashraf El-Meanawy; Ellen T McCarthy; Jianping Zhou; Varun C Boinpelly; Ram Sharma; Virginia J Savin; Mukut Sharma Journal: Am J Physiol Renal Physiol Date: 2020-07-06