On the participation of mTOR in recognition memory Jociane C. Myskiw, Janine I. Rossato, Lia R.M. Bevilaqua, Jorge H. Medina, Iva ´n Izquierdo, Martı ´n Cammarota * Centro de Memo ´ ria, Instituto de Pesquisas Biome ´dicas, Pontifı ´cia Universidade Cato ´ lica do Rio Grande do Sul, Av. Ipiranga 6690, Porto Alegre, RS 90610–000, Brazil Laboratorio de Neuroreceptores, Instituto de Biologı ´a Celular y Neurociencias ‘‘Prof. Dr. Eduardo de Robertis’’, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155 3° Piso, Ciudad Auto ´ noma de Buenos Aires, CP 1121, Argentina Received 26 September 2007; accepted 3 October 2007 Available online 26 November 2007 Abstract Evidence indicates that activation of the neuronal protein synthesis machinery is required in areas of the brain relevant to mem- ory for consolidation and persistence of the mnemonic trace. Here, we report that inhibition of hippocampal mTOR, a protein kinase involved in the initiation of mRNA translation, immediately or 180 min but not 540 min after training impairs consolidation of long-term object recognition memory without affecting short-term memory retention or exploratory behavior. When infused into dorsal CA1 after long-term memory reactivation in the presence of familiar objects the mTOR inhibitor rapamycin (RAP) did not affect retention. However, when given immediately after exposing animals to a novel and a familiar object, RAP impaired memory for both of them. The amnesic effect of the post-retrieval administration of RAP was long-lasting, did not happen after exposure to two novel objects or following exploration of the training arena in the absence of other stimuli, suggesting that it was contin- gent with reactivation of the consolidated trace in the presence of a behaviorally relevant and novel cue. Our results indicate that mTOR activity is required in the dorsal hippocampus for consolidation of object recognition memory and suggest that inhibition of this kinase after memory retrieval in the presence of a particular set of cues hinders persistence of the original recognition mem- ory trace. Ó 2007 Elsevier Inc. All rights reserved. Keywords: Memory; Object recognition; Consolidation; Reconsolidation; mTOR; Rapamycin; Hippocampus; Protein synthesis; Learning 1. Introduction New memories are initially fragile but, over time, con- solidate through a protein synthesis-dependent process that makes them resilient to disruption (Izquierdo & McGaugh, 2000; McGaugh, 2000; Izquierdo, Bevilaqua, Rossato, Bonini, Da Silva, Medina and Cammarota, 2006). Notwithstanding that, upon retrieval, many con- solidated memories are rendered again vulnerable to the action of metabolic blockers, notably protein synthesis inhibitors, suggesting the existence of a protein synthe- sis-dependent process that operates to re-stabilize the reactivated trace (Judge & Quartermain, 1982; Milekic & Alberini, 2002; Nader, Schafe, & Le Doux, 2000; Przybyslawski & Sara, 1997; Tronson & Taylor, 2007). Therefore, signaling pathways controlling mRNA transla- tion are likely to be involved in memory consolidation as well as in persistence of the trace after retrieval (Jacinto & Hall, 2003; Matthies, 1989; Raught, Gingras, & Sonenberg, 2001; Steward & Schuman, 2001; Bekinsch- tein, Cammarota, Igaz, Bevilaqua, Izquierdo and Med- ina, 2007a). The mammalian target of rapamycin (mTOR) is a serine–threonine protein kinase that acts as a down- stream mediator of the PI3K/Akt pathway, modulating 1074-7427/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.nlm.2007.10.002 * Corresponding author. Fax: +55 51 3320 3312. E-mail address: mcammaro@terra.com.br (M. Cammarota). www.elsevier.com/locate/ynlme Available online at www.sciencedirect.com Neurobiology of Learning and Memory 89 (2008) 338–351