Inhibition of mTOR by rapamycin in the amygdala or hippocampus impairs formation and reconsolidation of inhibitory avoidance memory

Jobim, Paulo Fernandes Costa; Pedroso, Thiago Rodrigues; Christoff, Raissa R.; Werenicz, Aline; Maurmann, Natasha; Reolon, Gustavo Kellermann; Roesler, Rafaël

doi:10.1016/j.nlm.2011.10.002

Cited by 83 publications

(72 citation statements)

References 40 publications

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“…Furthermore, mTORC1 is implicated in synaptic function and memory (Costa-Mattioli et al, 2009;Kelleher et al, 2004). Previous behavioral studies showed that rapamycin treatment impaired LTM but not STM, which is consistent with the present findings, in which AMPK was found to be crucial for LTM formation but not STM (Jobim et al, 2012). In the present study, we also found that AMPK dephosphorylation in the CA1 after contextual fear conditioning was associated with an increase in p70s6k phosphorylation.…”

Section: Discussionsupporting

confidence: 93%

AMPK Signaling in the Dorsal Hippocampus Negatively Regulates Contextual Fear Memory Formation

Han

Luo

Sun

et al. 2015

Neuropsychopharmacol

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Both the formation of long-term memory (LTM) and dendritic spine growth that serves as a physical basis for the long-term storage of information require de novo protein synthesis. Memory formation also critically depends on transcription. Adenosine monophosphateactivated protein kinase (AMPK) is a transcriptional regulator that has emerged as a major energy sensor that maintains cellular energy homeostasis. However, still unknown is its role in memory formation. In the present study, we found that AMPK is primarily expressed in neurons in the hippocampus, and then we demonstrated a time-dependent decrease in AMPK activity and increase in mammalian target of rapamycin complex 1 (mTORC1) activity after contextual fear conditioning in the CA1 but not CA3 area of the dorsal hippocampus. Using pharmacological methods and adenovirus gene transfer to bidirectionally regulate AMPK activity, we found that increasing AMPK activity in the CA1 impaired the formation of long-term fear memory, and decreasing AMPK activity enhanced fear memory formation. These findings were associated with changes in the phosphorylation of AMPK and p70s6 kinase (p70s6k) and expression of BDNF and membrane GluR1 and GluR2 in the CA1. Furthermore, the prior administration of an mTORC1 inhibitor blocked the enhancing effect of AMPK inhibition on fear memory formation, suggesting that this negative regulation of contextual fear memory by AMPK in the CA1 depends on the mTORC1 signaling pathway. Finally, we found that AMPK activity regulated hippocampal spine growth associated with memory formation. In summary, our results indicate that AMPK is a key negative regulator of plasticity and fear memory formation.

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Section: Discussionsupporting

confidence: 93%

AMPK Signaling in the Dorsal Hippocampus Negatively Regulates Contextual Fear Memory Formation

Han

Luo

Sun

et al. 2015

Neuropsychopharmacol

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“…In adult brain mTORC1 regulates protein synthesis by activating p70 S6 kinase 1 and 2 (S6K1/2) and other unknown factors (Stoica et al 2011). Studies with the inhibitor rapamycin have established that mTORC1 is required for consolidation and reconsolidation of aversive LTM (Parsons et al 2006;Bekinschtein et al 2007;Stoica et al 2011;Jobim et al 2012). This is in agreement with an up-regulation of S6K1/2 phosphorylation 30-60 min after training (Parsons et al 2006;Bekinschtein et al 2007).…”

Section: Pi3kmentioning

confidence: 57%

The roles of protein kinases in learning and memory

2013

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In the adult mammalian brain, more than 250 protein kinases are expressed, but only a few of these kinases are currently known to enable learning and memory. Based on this information it appears that learning and memory-related kinases either impact on synaptic transmission by altering ion channel properties or ion channel density, or regulate gene expression and protein synthesis causing structural changes at existing synapses as well as synaptogenesis. Here, we review the roles of these kinases in short-term memory formation, memory consolidation, memory storage, retrieval, reconsolidation, and extinction. Specifically, we discuss the roles of calcium/calmodulin-dependent kinase II (CaMKII

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“…3). Accordingly, pharmacological, functional imaging, and lesioning studies indicate an important role for the dorsal hippocampus in the reconsolidation of contextual fear conditioning (Boccia et al 2010;Jobim et al 2012;Lee et al 2013;De Jaeger et al 2014). These findings may also be interpreted as additional evidence supporting a role for hippocampal NMDA receptors, particularly those containing the GluN2 subunit, in memory reconsolidation (Pedreira et al 2002;Lee et al 2006;Ribeiro et al 2013), as far as the agonist and the antagonist of the polyaminebinding site at the NMDAr improved and disrupted memory reconsolidation, respectively.…”

Section: Discussionmentioning

confidence: 80%

Spermidine-induced improvement of reconsolidation of memory involves calcium-dependent protein kinase in rats

et al. 2015

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In this study, we determined whether the calcium-dependent protein kinase (PKC) signaling pathway is involved in the improvement of fear memory reconsolidation induced by the intrahippocampal administration of spermidine in rats. Male Wistar rats were trained in a fear conditioning apparatus using a 0.4-mA footshock as an unconditioned stimulus. Twenty-four hours after training, animals were re-exposed to the apparatus in the absence of shock (reactivation session). Immediately after the reactivation session, spermidine (2 -200 pmol/site), the PKC inhibitor 3-[1-(dimethylaminopropyl)indol-3-yl]-4-(indol-3-yl) maleimide hydrochloride (GF 109203X, 0.3 -30 pg/site), the antagonist of the polyamine-binding site at the NMDA receptor, arcaine (0.2 -200 pmol/site), or the PKC activator phorbol 12-myristate 13-acetate (PMA, 0.02 -2 nmol/site) was injected. While the post-reactivation administration of spermidine (20 and 200 pmol/site) and PMA (2 nmol/site) improved memory reconsolidation, GF 109203X (1, 10, and 30 pg/site) and arcaine (200 pmol/site) impaired it. GF 109203X (0.3 pg/site) impaired memory reconsolidation in the presence of spermidine (200 pmol/site). PMA (0.2 nmol/site) prevented the arcaine (200 pmol/site)-induced impairment of memory reconsolidation. Anisomycin (2 mg/site) also impaired memory reconsolidation in the presence of spermidine (200 pmol/site). Drugs had no effect when they were administered in the absence of reactivation. These results suggest that the spermidine-induced enhancement of memory reconsolidation involves PKC activation.

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Inhibition of mTOR by rapamycin in the amygdala or hippocampus impairs formation and reconsolidation of inhibitory avoidance memory

Cited by 83 publications

References 40 publications

AMPK Signaling in the Dorsal Hippocampus Negatively Regulates Contextual Fear Memory Formation

AMPK Signaling in the Dorsal Hippocampus Negatively Regulates Contextual Fear Memory Formation

The roles of protein kinases in learning and memory

Spermidine-induced improvement of reconsolidation of memory involves calcium-dependent protein kinase in rats

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