Decreased rates of cerebral protein synthesis measured <i>in vivo</i> in a mouse model of Tuberous Sclerosis Complex: unexpected consequences of reduced tuberin

Saré, Rachel Michelle; Huang, Tung‐Jung; Burlin, Tom; Loutaev, Inna; Smith, Carolyn Beebe

doi:10.1111/jnc.14311

Cited by 6 publications

(12 citation statements)

References 19 publications

(27 reference statements)

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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 , 48 , as well as in a mouse model of Fragile X Syndrome, a neurodevelopmental disorder characterized by an upregulated mTORC1 signaling 49 . Finally, one study reported that rapamycin treatment in rats increased anxiety in a battery of tests without modifying phospho-S6K1 protein levels 10 .…”

Section: Discussionsupporting

confidence: 67%

Inhibition of mTOR signaling by genetic removal of p70 S6 kinase 1 increases anxiety-like behavior in mice

et al. 2021

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The mechanistic target of 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-like 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 developing novel compounds targeting anxiety.

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Section: Discussionsupporting

confidence: 67%

Inhibition of mTOR signaling by genetic removal of p70 S6 kinase 1 increases anxiety-like behavior in mice

et al. 2021

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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: 66%

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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“…To address whether these effects occur in the intact brain of the Tsc2 Djk +/− model, we applied the autoradiographic L-[1- 14 C]leucine method which allows for the simultaneous determination of rates of protein synthesis across all regions of brain. Our results showed reduced rates of cerebral protein synthesis (rCPS) throughout the brain ( Saré et al, 2018 ). Our results and those of the ex vivo study were contrary to the central dogma of TSC, and we thought it important to repeat these studies in another Tsc2 heterozygous model.…”

Section: Introductionmentioning

confidence: 70%

“…The remainder, (1 – λ i ), comes from proteolysis in the tissue (1). λ i was evaluated in WT and Tsc2 Djk +/− mice and published previously ( Saré et al, 2018 ).…”

Section: Methodsmentioning

confidence: 99%

“…The isoflurane condition mimicked the conditions used for surgical preparation of animals for rCPS studies. The control condition was to compare with our previously published Western blot studies on the C57BL/6J background ( Saré et al, 2018 ) and to determine whether prior isoflurane exposure might be altering pathways related to regulation of protein synthesis, thus leading to our counterintuitive results. Animals were decapitated and brains were rapidly dissected on ice into cerebellum, frontal cortex, striatum, thalamus, hippocampus, and parietal cortex and placed in preweighed Precellys lysis tubes (Bertin Corporation).…”

Section: Methodsmentioning

confidence: 99%

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Confirmation of Decreased Rates of Cerebral Protein SynthesisIn Vivoin a Mouse Model of Tuberous Sclerosis Complex

Saré

Torossian

Loutaev

et al. 2022

eNeuro

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Tuberous Sclerosis Complex (TSC) is an autosomal dominant disorder that results in intellectual disability and, in about 50% of patients, autism spectrum disorder. The protein products that are altered in TSC (TSC1 and TSC2) form a complex to inhibit the mammalian target of rapamycin (mTORC1) pathway. This pathway has been shown to affect the process of mRNA translation through its action on ribosomal protein S6 and 4-elongation binding protein 1. It is thought that mutations in the TSC proteins lead to upregulation of the mTORC1 pathway and consequently an increase in protein synthesis. Unexpectedly, our previous study of a mouse model of TSC (Tsc2 Djk+/ ) demonstrated decreased in vivo rates of protein synthesis throughout the brain. In the present study, we confirm those results in another Tsc2 +/mouse model, one with a different mutation locus and on a mixed background (Tsc2 Mjg+/-). We also examine mTORC1 signaling and possible effects of prior isoflurane anesthesia. Because measurements of protein synthesis rates in vivo require surgical preparation of the animal and anesthesia, we examine mTORC1 signaling pathways both under baseline conditions and following recovery from anesthesia. Our results demonstrate regionally selective effects of prior anesthesia. Overall, our results in both in vivo models suggest differences to the central hypothesis regarding TSC and show the importance of studying protein synthesis in vivo.

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Decreased rates of cerebral protein synthesis measured in vivo in a mouse model of Tuberous Sclerosis Complex: unexpected consequences of reduced tuberin

Cited by 6 publications

References 19 publications

Inhibition of mTOR signaling by genetic removal of p70 S6 kinase 1 increases anxiety-like behavior in mice

Inhibition of mTOR signaling by genetic removal of p70 S6 kinase 1 increases anxiety-like behavior in mice

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

Confirmation of Decreased Rates of Cerebral Protein SynthesisIn Vivoin a Mouse Model of Tuberous Sclerosis Complex

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