The mTORC1 inhibitor rapamycin and the mTORC1/2 inhibitor AZD2014 impair the consolidation and persistence of contextual fear memory.

Abstract

The mechanistic target of rapamycin (mTOR) kinase mediates various long-lasting forms of synaptic and behavioural plasticity. However, there is little information concerning the temporal pattern of mTOR activation and susceptibility to pharmacological intervention during consolidation of contextual fear memory. Moreover, the contribution of both mTOR complex 1 and 2 together or the mTOR complex 1 downstream effector p70S6K (S6K1) to consolidation of contextual fear memory is unknown. Here, we tested whether different timepoints of vulnerability to rapamycin, a first generation mTOR complex 1 inhibitor, exist for contextual fear memory consolidation and persistence. We also sought to characterize the effects of dually inhibiting mTORC1/2 as well as S6K1 on fear memory formation and persistence. Rapamycin was injected systemically to mice immediately, 3h, or 12h after contextual fear conditioning, and retention was measured at different timepoints thereafter. To determine the effects of a single injection of the dual mTROC1/2 inhibitor AZD2014 after learning on memory consolidation and persistence, a dose-response experiment was carried out. Memory formation and persistence was also assessed in response to the S6K1 inhibitor PF-4708671. A single systemic injection of rapamycin immediately or 3h, but not 12h, after learning impaired the formation and persistence of contextual fear memory. AZD2014 was found, with limitations, to dose-dependently attenuate memory consolidation and persistence at the highest dose tested (50mg/kg). In contrast, PF-4708671 had no effect on consolidation or persistence. Our results indicate the need to further understand the role of mTORC1/2 kinase activity in the molecular mechanisms underlying memory processing and also demonstrate that the effects of mTORC1 inhibition at different timepoints well after learning on memory consolidation and persistence.