title: Selective pharmacogenetic inhibition of mammalian target of Rapamycin complex I (mTORC1) blocks long-term synaptic plasticity and memory storage.
abstract: Both the formation of long-term memory (LTM) and late-long-term potentiation (L-LTP), which is thought to represent the cellular model of learning and memory, require de novo protein synthesis. The mammalian target of Rapamycin (mTOR) complex I (mTORC1) integrates information from various synaptic inputs and its best characterized function is the regulation of translation. Although initial studies have shown that rapamycin reduces L-LTP and partially blocks LTM, recent genetic and pharmacological evidence indicating that mTORC1 promotes L-LTP and LTM is controversial. Thus, the role of mTORC1 in L-LTP and LTM is unclear. To selectively inhibit mTORC1 activity in the adult brain, we used a "pharmacogenetic" approach that relies on the synergistic action of a drug (rapamycin) and a genetic manipulation (mTOR heterozygotes, mTOR(+/-) mice) on the same target (mTORC1). Although L-LTP and LTM are normal in mTOR(+/-) mice, application of a low concentration of rapamycin-one that is subthreshold for WT mice-prevented L-LTP and LTM only in mTOR(+/-) mice. Furthermore, we found that mTORC1-mediated translational control is required for memory reconsolidation. We provide here direct genetic evidence supporting the role of mTORC1 in L-LTP and behavioral memory.
authors.affiliation: Department of Neuroscience, Center for Addiction, Learning and Memory, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Loredana
authors.initials: L
authors.lastname: Stoica
authors.forename: Ping Jun
authors.initials: PJ
authors.lastname: Zhu
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.forename: Hongyi
authors.initials: H
authors.lastname: Zhou
authors.forename: Sara C
authors.initials: SC
authors.lastname: Kozma
authors.forename: Mauro
authors.initials: M
authors.lastname: Costa-Mattioli
mesh_terms: D000161:Acoustic Stimulation; D000818:Animals; D005239:Fear / Q000187:drug effects; D017774:Long-Term Potentiation / Q000187:drug effects*; D000076222:Mechanistic Target of Rapamycin Complex 1; D057567:Memory, Long-Term / Q000187:drug effects*; D051379:Mice; D046912:Multiprotein Complexes; D010597:Pharmacogenetics; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors
chemical_list: C504923:Crtc2 protein, mouse; D046912:Multiprotein Complexes; D011506:Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus