Blocking mTORC1 activity by rapamycin leads to impairment of spatial memory retrieval but not acquisition in C57BL/6J mice

Deli, Alev; Rosner, Margit; Höger, Harald; Pollak, Arnold; Li, Lin; Hengstschläger, Markus; Lubec, Gert

doi:10.1016/j.bbr.2012.01.017

Cited by 29 publications

(18 citation statements)

References 46 publications

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“…In addition, peripheral rapamycin injections in mice that have fully learned the accelerating rotarod task have no effect. This particular finding is supported by a previous study demonstrating that systemic administrations of rapamycin do not affect mice performances when they are pre-trained on the rotarod (Deli et al, 2012). Moreover, the fact that both systemic and intrastriatal treatments lead to similar results suggests that possible effects of mTOR inhibition on peripheral functions such as muscles strength are unlikely.…”

Section: Discussionsupporting

confidence: 80%

mTOR signaling contributes to motor skill learning in mice

Bergeron

Chagniel

Bureau

et al. 2014

Front. Mol. Neurosci.

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The mammalian target of rapamycin (mTOR) kinase is a critical regulator of mRNA translation and is suspected to be involved in various long-lasting forms of synaptic and behavioral plasticity. However, its role in motor learning and control has never been examined. This study investigated, in mice, the implication of mTOR in the learning processes associated with the accelerating rotarod task. We first observed that the rotarod learning did not alter the levels of total mTOR in the striatum, hippocampus, cerebellum, and anterior cortex of trained mice. However, it increased the levels of phosphorylated mTOR in the striatum and hippocampus exclusively during the first session of training; no change was observed at the second and third sessions. In order to further investigate the potential role of mTOR during motor skill learning, we performed systemic and intrastriatal inhibitions of mTOR using the pharmacological inhibitor rapamycin, as well as a genetic knockdown of striatal mTOR using intrastriatal infusion of mTOR siRNA. These three independent approaches were all associated with a significant reduction in rotarod performances that were reminiscent of impaired consolidation processes. Notably, these treatments did not affect the capacity of mice to execute the pole test, suggesting that mTOR activity was mainly controlling motor learning rather than motor abilities. Moreover, all treatments decreased the levels of phosphorylated 4EBP1 and P70S6K, two molecular downstream targets of mTORC1. Our findings demonstrate that striatal mTOR kinase, via the phosphorylation of 4EBP1 and P70S6K, plays an important role in the cellular and molecular processes involved in motor skill learning.

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Section: Discussionsupporting

confidence: 80%

mTOR signaling contributes to motor skill learning in mice

Bergeron

Chagniel

Bureau

et al. 2014

Front. Mol. Neurosci.

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“…Avoidance and contextual freezing subsequently tested in the absence of inhibitor are normal, indicating that the effect of the inhibitor is transient. Similar results for inhibitory avoidance, contextual fear and/or spatial memory were obtained with inhibitors of phosphatidylinositol 3‐OH kinase (PI3K), Jun N‐terminal kinase (JNK), glycogen synthase kinase‐3β (GSK‐3β) and mammalian target of rapamycin (mTOR), suggesting that signaling by these kinases may also be required for retrieval (Bevilaqua et al, ; Chen et al, ; Deli et al, ; Hong et al, ).…”

Section: Neuromodulatory Roles In Retrievalmentioning

confidence: 62%

Neuromodulatory signaling in hippocampus‐dependent memory retrieval

Thomas

2015

Hippocampus

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Considerable advances have been made toward understanding the molecular signaling events that underlie memory acquisition and consolidation. In contrast, less is known about memory retrieval, despite its necessity for utilizing learned information. This review focuses on neuromodulatory and intracellular signaling events that underlie memory retrieval mediated by the hippocampus, for which the most information is currently available. Among neuromodulators, adrenergic signaling is required for the retrieval of various types of hippocampus-dependent memory. Although they contribute to acquisition and/or consolidation, cholinergic and dopaminergic signaling are generally not required for retrieval. Interestingly, while not required for retrieval, serotonergic and opioid signaling may actually constrain memory retrieval. Roles for histamine and non-opioid neuropeptides are currently unclear but possible. A critical effector of adrenergic signaling in retrieval is reduction of the slow afterhyperpolarization mediated by β1 receptors, cyclic AMP, protein kinase A, Epac, and possibly ERK. In contrast, stress and glucocorticoids impair retrieval by decreasing cyclic AMP, mediated in part by the activation of β2 -adrenergic receptors. Clinically, alterations in neuromodulatory signaling and in memory retrieval occur in Alzheimer's disease, Down syndrome, depression, and post-traumatic stress disorder, and recent evidence has begun to link changes in neuromodulatory signaling with effects on memory retrieval.

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“…Thus, given the important role of mTORC1 in controlling protein synthesis, it is not surprising that inhibiting mTORC1 with rapamycin blocks longterm memory formation in a number of paradigms (Tischmeyer et al 2003;Parsons et al 2006;Bekinschtein et al 2007;Blundell et al 2008;Belelovsky et al 2009;Glover et al 2010;Gafford et al 2011;Deli et al 2012;Halloran et al 2012;Jobim et al 2012). Probably the most convincing evidence uses a mTOR heterozygotic mouse to show that both consolidation and reconsolidation of memories are blocked at lower concentrations of rapamycin, directly tying the actions of rapamycin on memory to mTOR (Stoica et al 2011).…”

Section: Mtorc1 Synaptic Plasticity and Memorymentioning

confidence: 99%

A recollection of mTOR signaling in learning and memory

2013

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Mechanistic target of rapamcyin (mTOR) is a central player in cell growth throughout the organism. However, mTOR takes on an additional, more specialized role in the developed neuron, where it regulates the protein synthesis-dependent, plastic changes underlying learning and memory. mTOR is sequestered in two multiprotein complexes (mTORC1 and mTORC2) that have different substrate specificities, thus allowing for distinct functions at synapses. We will examine how learning activates the mTOR complexes, survey the critical effectors of this pathway in the context of synaptic plasticity, and assess whether mTOR plays an instructive or permissive role in generating molecular memory traces.

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Blocking mTORC1 activity by rapamycin leads to impairment of spatial memory retrieval but not acquisition in C57BL/6J mice

Cited by 29 publications

References 46 publications

mTOR signaling contributes to motor skill learning in mice

mTOR signaling contributes to motor skill learning in mice

Neuromodulatory signaling in hippocampus‐dependent memory retrieval

A recollection of mTOR signaling in learning and memory

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