title: mTORC1-S6K1 inhibition or mTORC2 activation improves hippocampal synaptic plasticity and learning in Angelman syndrome mice.
abstract: 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 PKCα 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.
authors.affiliation: Department of Basic Medical Sciences, COMP, Western University of Health Sciences, 701 E. Second Street, Pomona, CA, 91766-1854, USA.
authors.forename: Jiandong
authors.initials: J
authors.lastname: Sun
authors.affiliation: Graduate College of Biomedical Sciences, Western University of Health Sciences, 701 E. Second Street, Pomona, CA, 91766, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Basic Medical Sciences, COMP, Western University of Health Sciences, 701 E. Second Street, Pomona, CA, 91766-1854, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Tran
authors.affiliation: Department of Basic Medical Sciences, COMP, Western University of Health Sciences, 701 E. Second Street, Pomona, CA, 91766-1854, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: O'Neal
authors.affiliation: Graduate College of Biomedical Sciences, Western University of Health Sciences, 701 E. Second Street, Pomona, CA, 91766, USA.
authors.forename: Michel
authors.initials: M
authors.lastname: Baudry
authors.affiliation: Department of Basic Medical Sciences, COMP, Western University of Health Sciences, 701 E. Second Street, Pomona, CA, 91766-1854, USA. xbi@westernu.edu.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Bi
mesh_terms: D000199:Actins / Q000378:metabolism; D017204:Angelman Syndrome / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D001798:Blood Proteins / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007858:Learning / Q000187:drug effects; D017774:Long-Term Potentiation / Q000187:drug effects; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D058105:Polymerization / Q000187:drug effects; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: C504035:A 443654; D000199:Actins; D001798:Blood Proteins; D003598:Cytoskeletal Proteins; D007093:Imidazoles; D007191:Indazoles; D007211:Indoles; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; C552719:PF-4708671; D010879:Piperazines; C092069:activity regulated cytoskeletal-associated protein; C031024:torin; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D020123:Sirolimus
keywords: Cognitive deficits; Dendritic spine; GluA1; Phosphorylation; S6K1 inhibitor; Translation; mTORC2 activator