Acute systemic rapamycin induces neurobehavioral alterations in rats

Hadamitzky, Martin; Herring, Arne; Keyvani, Kathy; Doenlen, Raphaël; Krügel, Ute; Bösche, Katharina; Orlowski, Kathrin; Engler, Harald; Schedlowski, Manfred

doi:10.1016/j.bbr.2014.06.056

Cited by 40 publications

(32 citation statements)

References 49 publications

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“…For instance, chronic rapamycin treatment improved anxiety-like behaviors throughout lifespan in mice 17 , whereas treatment of male mice with the rapamycin analog everolimus induces anxiety-like behavior 11 . Consistent with this latter result, chronic treatment with rapamycin had anxiogenic effects in male rats 10,39 , as well as in a mouse model of Fragile X Syndrome, a neurodevelopmental disorder characterized by an upregulated mTORC1 signaling 40 .…”

Section: Discussionsupporting

confidence: 65%

Inhibition of mTOR signaling by genetic removal of p70 S6 Kinase 1 leads to anxiety-like disorders

Koehl

Ladevèze

Catania

et al. 2020

Preprint

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The mechanistic target or rapamycin (mTOR) is a ubiquitously expressed kinase that acts through two complexes, mTORC1 and mTORC2, to regulate protein homeostasis as well as long lasting forms of synaptic and behavioral plasticity. Alteration of the mTOR pathway is classically involved in neurodegenerative disorders, and it has been linked to dysregulation of cognitive functions and affective states. However, information concerning the specific involvement of the p70 S6 kinase 1 (S6K1), a downstream target of the mTORC1 pathway, in learning and memory processes and in the regulation of affective states remains scant. To fill this gap, we exposed adult male mice lacking S6K1 to a battery of behavioral tests aimed at measuring their learning and memory capabilities by evaluating reference memory and flexibility with the Morris water maze, and associative memory using the contextual fear conditioning task. We also studied their anxiety-and depression-like behaviors by respectively performing elevated plus maze, open field, light-dark emergence tests, and sucrose preference and forced swim tests. We found that deleting S6K1 leads to a robust anxious phenotype concomitant with associative learning deficits; these symptoms are associated with a reduction of adult neurogenesis and neuronal atrophy in the hippocampus. Collectively, these results provide grounds for the understanding of anxiety reports after treatments with mTOR inhibitors and will be critical for the development of novel compounds targeting anxiety.

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Section: Discussionsupporting

confidence: 65%

Inhibition of mTOR signaling by genetic removal of p70 S6 Kinase 1 leads to anxiety-like disorders

Koehl

Ladevèze

Catania

et al. 2020

Preprint

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“…For gene expression analysis, animals were sacrificed 60 min following either the 3rd or the 6th CS reexposure and c-fos mRNA expression was quantified in amygdala and insular cortex tissue samples by real-time quantitative PCR as shown previously (Hadamitzky et al, 2014). After decapitation, brains were quickly removed, frozen on dry ice, and stored at À80°C until further processing.…”

Section: Gene Expression Analysismentioning

confidence: 99%

Extinction of conditioned taste aversion is related to the aversion strength and associated with c-fos expression in the insular cortex

et al. 2015

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“…It is assumed that rapamycin may play a role in regulating the negative feedback loops emanating from the PIC signaling pathway. Although it still needs more mechanistic evidence to support this possibility, this raises an issue of how rapamycin influences neuronal activity and neurological functions [19]. Nonetheless, it needs be acknowledged that there are some study limitations in our present report.Those include that we did not determine the effects of rapamycin on cognitive function in normal rats, and that we did not determine if rapamycin can affect the endogenous levels of Aβ linked to cognitive function since we injected Aβ via ICV.…”

Section: Discussionmentioning

confidence: 84%

“…The size of rapamycin dosage can affect neuronal activity and neurological functions differently. It has been reported that acute administration of a low dose of rapamycin adulterates neuronal activity in rats which contribute to the development of neurological behavior such as cognitive functions [19],raising a question of how rapamycin can alter neurological functions. Taken together, the different effects of rapamycin on cognitive functions observed in our study and others’ reports could be due to dosages of rapamycin and their administration pathways, animal species and ages.…”

Section: Discussionmentioning

confidence: 99%

Cerebral mTOR signal and pro-inflammatory cytokines in Alzheimer’s disease rats

Wang

et al. 2016

Translational Neuroscience

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As a part of Alzheimer’s disease (AD) development the mammalian target of rapamycin (mTOR) has been reported to play a crucial role in regulating cognition and can be used as a neuronal marker. Neuro-inflammation is also a cause of the pathophysiological process in AD. Thus, we examined the protein expression levels of mTOR and its downstream pathways as well as pro-inflammatory cytokines (PICs) in the brain of AD rats. We further examined the effects of blocking mTOR on PICs, namely IL-1β, IL-6 and TNF-α. Our results showed that the protein expression of p-mTOR, mTOR-mediated phosphorylation of 4E-binding protein 4 (4E-BP1) and p70 ribosomal S6 protein kinase 1 (S6K1) pathways were amplified in the hippocampus of AD rats compared with controls. Blocking mTOR by using rapamycin selectively enhanced activities of IL-6 and TNF-α signaling pathways, which was accompanied with an increase of Caspase-3, indicating cellular apoptosis and worsened learning performance. In conclusion, our data for the first time revealed specific signaling pathways engaged in the development of AD, including a regulatory role by the activation of mTOR in PIC mechanisms. Stimulation of mTOR is likely to play a beneficial role in modulating neurological deficits in AD.Targeting one or more of these signaling molecules may present with new opportunities for treatment and clinical management of AD

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Acute systemic rapamycin induces neurobehavioral alterations in rats

Cited by 40 publications

References 49 publications

Inhibition of mTOR signaling by genetic removal of p70 S6 Kinase 1 leads to anxiety-like disorders

Inhibition of mTOR signaling by genetic removal of p70 S6 Kinase 1 leads to anxiety-like disorders

Extinction of conditioned taste aversion is related to the aversion strength and associated with c-fos expression in the insular cortex

Cerebral mTOR signal and pro-inflammatory cytokines in Alzheimer’s disease rats

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