title: Systemic inhibition of mTOR kinase via rapamycin disrupts consolidation and reconsolidation of auditory fear memory.
abstract: The mammalian target of rapamycin (mTOR) kinase is a critical regulator of mRNA translation and is known to be involved in various long lasting forms of synaptic and behavioural plasticity. However, information concerning the temporal pattern of mTOR activation and susceptibility to pharmacological intervention during both consolidation and reconsolidation of long-term memory (LTM) remains scant. Male C57BL/6 mice were injected systemically with rapamycin at various time points following conditioning or retrieval in an auditory fear conditioning paradigm, and compared to vehicle (and/or anisomycin) controls for subsequent memory recall. Systemic blockade of mTOR with rapamycin immediately or 12h after training or reactivation impairs both consolidation and reconsolidation of an auditory fear memory. Further behavioural analysis revealed that the enduring effects of rapamycin on reconsolidation are dependent upon reactivation of the memory trace. Rapamycin, however, has no effect on short-term memory or the ability to retrieve an established fear memory. Collectively, our data suggest that biphasic mTOR signalling is essential for both consolidation and reconsolidation-like activities that contribute to the formation, re-stabilization, and persistence of long term auditory-fear memories, while not influencing other aspects of the memory trace. These findings also provide evidence for a cogent treatment model for reducing the emotional strength of established, traumatic memories analogous to those observed in acquired anxiety disorders such as posttraumatic stress disorder (PTSD) and specific phobias, through pharmacologic blockade of mTOR using systemic rapamycin following reactivation.
authors.affiliation: Department of Psychology, Memorial University of Newfoundland, 232 Elizabeth Ave., St. John's, Newfoundland A1B 3X9, Canada.
authors.forename: Phillip E
authors.initials: PE
authors.lastname: Mac Callum
authors.affiliation: Department of Psychology, Memorial University of Newfoundland, 232 Elizabeth Ave., St. John's, Newfoundland A1B 3X9, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Hebert
authors.affiliation: Department of Psychology, Memorial University of Newfoundland, 232 Elizabeth Ave., St. John's, Newfoundland A1B 3X9, Canada.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Adamec
authors.affiliation: Department of Psychology, Memorial University of Newfoundland, 232 Elizabeth Ave., St. John's, Newfoundland A1B 3X9, Canada. Electronic address: jblundell@mun.ca.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Blundell
mesh_terms: D000818:Animals; D001307:Auditory Perception / Q000502:physiology; D003214:Conditioning, Classical / Q000502:physiology; D005239:Fear / Q000502:physiology*; D008297:Male; D057567:Memory, Long-Term / Q000187:drug effects*; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D013997:Time Factors
chemical_list: D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Auditory fear memory; Consolidation; Posttraumatic stress disorder; Rapamycin; Reconsolidation; mTOR