PMID- 27173058 OWN - NLM STAT- MEDLINE DCOM- 20170804 LR - 20240213 IS - 1420-9071 (Electronic) IS - 1420-682X (Print) IS - 1420-682X (Linking) VI - 73 IP - 22 DP - 2016 Nov TI - mTORC1-S6K1 inhibition or mTORC2 activation improves hippocampal synaptic plasticity and learning in Angelman syndrome mice. PG - 4303-4314 AB - Emerging evidence is implicating abnormal activation of the mechanistic target of rapamycin (mTOR) pathway in several monogenetic neuropsychiatric disorders, including Angelman syndrome (AS), which is caused by deficiency in maternally inherited UBE3A. Using an AS mouse model, we show that semi-chronic rapamycin treatment improves long-term potentiation (LTP) and actin polymerization in hippocampal slices, spine morphology, and fear-conditioning learning. Activity of mTORC1 and of its downstream substrate, S6K1, was increased in hippocampus of AS mice. However, mTORC2 activity, as reflected by PKCalpha levels, was decreased. Both increased mTORC1 and decreased mTORC2 activities were reversed by semi-chronic rapamycin treatment. Acute treatment of hippocampal slices from AS mice with rapamycin or an S6K1 inhibitor, PF4708671, improved LTP, restored actin polymerization, and normalized mTORC1 and mTORC2 activity. These treatments also reduced Arc levels in AS mice. Treatment with Torin 1, an inhibitor of both mTORC1 and mTORC2, partially rescued LTP and actin polymerization in hippocampal slices from AS mice, while partially impairing them in wild-type (WT) mice. Torin 1 decreased mTORC1 and increased mTORC2 activity in slices from AS mice but inhibited both mTORC1 and mTORC2 in WT mice. Finally, an mTORC2 activator, A-443654, increased hippocampal LTP in AS mice and actin polymerization in both WT and AS mice. Collectively, these results indicate that events set in motion by increased mTORC1 and decreased mTORC2 activities, including increased Arc translation and impaired actin remodeling, are crucial in AS pathogenesis. Therefore, selectively targeting these two master kinase complexes may provide new therapeutic approaches for AS treatment. FAU - Sun, Jiandong AU - Sun J AD - Department of Basic Medical Sciences, COMP, Western University of Health Sciences, 701 E. Second Street, Pomona, CA, 91766-1854, USA. FAU - Liu, Yan AU - Liu Y AD - Graduate College of Biomedical Sciences, Western University of Health Sciences, 701 E. Second Street, Pomona, CA, 91766, USA. FAU - Tran, Jennifer AU - Tran J AD - Department of Basic Medical Sciences, COMP, Western University of Health Sciences, 701 E. Second Street, Pomona, CA, 91766-1854, USA. FAU - O'Neal, Patrick AU - O'Neal P AD - Department of Basic Medical Sciences, COMP, Western University of Health Sciences, 701 E. Second Street, Pomona, CA, 91766-1854, USA. FAU - Baudry, Michel AU - Baudry M AD - Graduate College of Biomedical Sciences, Western University of Health Sciences, 701 E. Second Street, Pomona, CA, 91766, USA. FAU - Bi, Xiaoning AU - Bi X AD - Department of Basic Medical Sciences, COMP, Western University of Health Sciences, 701 E. Second Street, Pomona, CA, 91766-1854, USA. xbi@westernu.edu. LA - eng GR - P01 NS045260/NS/NINDS NIH HHS/United States GR - R01 NS057128/NS/NINDS NIH HHS/United States GR - R15 MH101703/MH/NIMH NIH HHS/United States PT - Journal Article DEP - 20160512 PL - Switzerland TA - Cell Mol Life Sci JT - Cellular and molecular life sciences : CMLS JID - 9705402 RN - 0 (A 443654) RN - 0 (Actins) RN - 0 (Blood Proteins) RN - 0 (Cytoskeletal Proteins) RN - 0 (Imidazoles) RN - 0 (Indazoles) RN - 0 (Indoles) RN - 0 (Multiprotein Complexes) RN - 0 (Nerve Tissue Proteins) RN - 0 (PF-4708671) RN - 0 (Piperazines) RN - 0 (activity regulated cytoskeletal-associated protein) RN - 0 (torin) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.1 (ribosomal protein S6 kinase, 70kD, polypeptide 1) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Actins/metabolism MH - Angelman Syndrome/metabolism/*physiopathology MH - Animals MH - Blood Proteins/pharmacology MH - Cytoskeletal Proteins/metabolism MH - Hippocampus/drug effects/*physiopathology MH - Imidazoles/pharmacology MH - Indazoles/pharmacology MH - Indoles/pharmacology MH - *Learning/drug effects MH - Long-Term Potentiation/drug effects MH - Mechanistic Target of Rapamycin Complex 1 MH - Mechanistic Target of Rapamycin Complex 2 MH - Mice MH - Multiprotein Complexes/*antagonists & inhibitors/*metabolism MH - Nerve Tissue Proteins/metabolism MH - *Neuronal Plasticity/drug effects MH - Piperazines/pharmacology MH - Polymerization/drug effects MH - Ribosomal Protein S6 Kinases, 70-kDa/*antagonists & inhibitors/metabolism MH - Signal Transduction/drug effects MH - Sirolimus/pharmacology MH - TOR Serine-Threonine Kinases/*antagonists & inhibitors/*metabolism PMC - PMC5056144 MID - NIHMS805686 OTO - NOTNLM OT - Cognitive deficits OT - Dendritic spine OT - GluA1 OT - Phosphorylation OT - S6K1 inhibitor OT - Translation OT - mTORC2 activator COIS- The authors declare no conflict of interest. EDAT- 2016/05/14 06:00 MHDA- 2017/08/05 06:00 PMCR- 2017/05/01 CRDT- 2016/05/14 06:00 PHST- 2016/03/21 00:00 [received] PHST- 2016/05/06 00:00 [accepted] PHST- 2016/04/27 00:00 [revised] PHST- 2016/05/14 06:00 [pubmed] PHST- 2017/08/05 06:00 [medline] PHST- 2016/05/14 06:00 [entrez] PHST- 2017/05/01 00:00 [pmc-release] AID - 10.1007/s00018-016-2269-z [pii] AID - 10.1007/s00018-016-2269-z [doi] PST - ppublish SO - Cell Mol Life Sci. 2016 Nov;73(22):4303-4314. doi: 10.1007/s00018-016-2269-z. Epub 2016 May 12.