mTORC2, but not mTORC1, is required for hippocampal mGluR-LTD and associated behaviors

Zhu, Ping; Chen, Chien-Ju; Mays, Jacqunae; Stoica, Loredana Elena; Costa-Mattioli, Mauro

doi:10.1038/s41593-018-0156-7

Cited by 59 publications

(50 citation statements)

References 25 publications

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“…Whereas mTOR complex 1 (mTORC1) is a master regulator of cap-dependent translation (Darnell and Klann, 2013), mTORC2 is a central regulator of the actin cytoskeleton through its actions on the actin-depolymerizing factor cofilin (Costa-Mattioli and Monteggia, 2013; Laplante and Sabatini, 2012; see also below). Moreover, mTORC2 (but not mTORC1) has been shown to be critical to mGluR-LTD and related behaviors (Zhu et al, 2018).…”

Section: Molecular Signalingmentioning

confidence: 99%

A Synaptic Perspective of Fragile X Syndrome and Autism Spectrum Disorders

Bagni

Zukin

2019

Neuron

250

258

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Altered synaptic structure and function is a major hallmark of fragile X syndrome (FXS), autism spectrum disorders (ASDs), and other intellectual disabilities (IDs), which are therefore classified as synaptopathies. FXS and ASDs, while clinically and genetically distinct, share significant comorbidity, suggesting that there may be a common molecular and/or cellular basis, presumably at the synapse. In this article, we review brain architecture and synaptic pathways that are dysregulated in FXS and ASDs, including spine architecture, signaling in synaptic plasticity, local protein synthesis, (m)RNA modifications, and degradation. mRNA repression is a powerful mechanism for the regulation of synaptic structure and efficacy. We infer that there is no single pathway that explains most of the etiology and discuss new findings and the implications for future work directed at improving our understanding of the pathogenesis of FXS and related ASDs and the design of therapeutic strategies to ameliorate these disorders. ASDs and FXS: Causes and Clinical Features Approximately 1%-3% of the general population is affected by intellectual disabilities (IDs). IDs are neurodevelopmental disorders defined by significant limitations in intellectual functioning and adaptive behaviors and often exhibit comorbidity with autism (Mefford et al., 2012). Autism spectrum disorders (ASDs) are characterized by high phenotypic heterogeneity, comprising deficits in social interaction and communication as well as repetitive and stereotyped behaviors (

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Section: Molecular Signalingmentioning

confidence: 99%

A Synaptic Perspective of Fragile X Syndrome and Autism Spectrum Disorders

Bagni

Zukin

2019

Neuron

250

258

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“…It is well known that rapamycin blocks hippocampal mGluR-LTD (Hou and Klann, 2004), initially suggesting that protein synthesis mediated by mTORC1 is necessary for this plasticity. Nevertheless, chronic treatment or high concentrations of rapamycin also inhibit mTORC2 (Sarbassov et al, 2006), and, moreover, it has been recently reported that mTORC2, but not mTORC1, is required for mGluR-LTD (Zhu et al, 2018). In line with these results, it is well established that inhibiting actin polymerization/depolymerization blocks mGluR-LTD (Zhou et al, 2011) and that dendritic spines elongate in response to mGluR activation, correlating with AMPA receptor (AMPAR) endocytosis (Vanderklish and Edelman, 2002;Zhou et al, 2011).…”

Section: Introductionmentioning

confidence: 81%

“…The relative contribution of these cascades to the protein synthesis necessary for mGluR-LTD is nevertheless unclear (for a review see Bhakar et al 2012). Interestingly, it has been recently shown that mTORC2, but not mTORC1, is required for mGluR-LTD (Zhu et al, 2018). mTORC2 regulates actin cytoskeleton and, in fact, actin polymerization-depolymerization inhibition abolishes mGluR-LTD (Zhou et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, novelty and spatial recognition of objects engage mGluR-LTD Manahan-Vaughan, 2013a, 2013b) It is also well known that mTOR is involved in this type of plasticity (Hou and Klann, 2004;Zhu et al, 2018) and, remarkably, mTOR is hyperactivated in Ts1Cje hippocampus (Troca-Marín et al, 2011). Altogether, these data stimulated us to evaluate mGluR-LTD in Ts1Cje mice.…”

Section: Mglur-ltd Is Enhanced In the Ca1 Region Of Ts1cje Hippocampusmentioning

confidence: 99%

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Prenatal treatment with rapamycin restores enhanced hippocampal mGluR-LTD and mushroom spine size in a Down’s syndrome mouse model

Montesinos

Urbano-Gámez

Benito

et al. 2020

Preprint

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Down syndrome (DS) is the most frequent genetic cause of intellectual disability including hippocampal-dependent memory deficits. We have previously reported hippocampal mTOR (mammalian target of rapamycin) hyperactivation, and related plasticity as well as memory deficits in Ts1Cje mice, a DS experimental model. Here we report that performance of Ts1Cje mice in novel object recognition (NOR) is impaired, but it is ameliorated by rapamycin treatment. Proteome characterization of hippocampal synaptoneurosomes (SNs) from these mice predicted an alteration of synaptic plasticity pathways, including long term depression (LTD), which was reversed by rapamycin. Accordingly, mGluR-LTD (metabotropic Glutamate Receptor-Long Term Depression) is enhanced in the hippocampus of Ts1Cje mice and this is correlated with an increased proportion of a particular category of mushroom spines in hippocampal pyramidal neurons. Remarkably, prenatal treatment of these mice with rapamycin normalized both phenotypes, supporting the therapeutic potential of rapamycin/rapalogs for DS intellectual disability.

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“…For example, Tsc2 +/− mice have reduced hippocampal protein synthesis rates instead of the predicted excessive protein synthesis from mTOR hyperactivation [2]. In addition, a recent study challenged the role of mTORC1 in hippocampal mGluR-LTD, arguing that mTORC2 is the major regulator of this form of synaptic plasticity [18,19] but see [13,20]. MGluR1/5 signaling can also regulate translation factors to suppress global protein synthesis, such as phosphorylation of eukaryotic initiation factor 2 alpha and eukaryotic elongation factor 2 (eEF2), which are both necessary for mGluR-LTD [18,21].…”

Section: Introductionmentioning

confidence: 99%

Ribosome profiling in mouse hippocampus: plasticity-induced regulation and bidirectional control by TSC2 and FMRP

et al. 2020

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Background Mutations in TSC2 are the most common cause of tuberous sclerosis (TSC), a disorder with a high incidence of autism and intellectual disability. TSC2 regulates mRNA translation required for group 1 metabotropic glutamate receptor-dependent synaptic long-term depression (mGluR-LTD) and behavior, but the identity of mRNAs responsive to mGluR-LTD signaling is largely unknown. Methods We utilized Tsc2+/− mice as a mouse model of TSC and prepared hippocampal slices from these animals. We induced mGluR-LTD synaptic plasticity in slices and processed the samples for RNA-seq and ribosome profiling to identify differentially expressed genes in Tsc2+/− and following mGluR-LTD synaptic plasticity. Results Ribosome profiling reveals that in Tsc2+/− mouse hippocampal slices, the expression of several mRNAs was dysregulated: terminal oligopyrimidine (TOP)-containing mRNAs decreased, while FMRP-binding targets increased. Remarkably, we observed the opposite changes of FMRP binding targets in Fmr1−/y hippocampi. In wild-type hippocampus, induction of mGluR-LTD caused rapid changes in the steady-state levels of hundreds of mRNAs, many of which are FMRP targets. Moreover, mGluR-LTD failed to promote phosphorylation of eukaryotic elongation factor 2 (eEF2) in TSC mice, and chemically mimicking phospho-eEF2 with low cycloheximide enhances mGluR-LTD in TSC mice. Conclusion These results suggest a molecular basis for bidirectional regulation of synaptic plasticity and behavior by TSC2 and FMRP. Our study also suggests that altered mGluR-regulated translation elongation contributes to impaired synaptic plasticity in Tsc2+/− mice.

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mTORC2, but not mTORC1, is required for hippocampal mGluR-LTD and associated behaviors

Cited by 59 publications

References 25 publications

A Synaptic Perspective of Fragile X Syndrome and Autism Spectrum Disorders

A Synaptic Perspective of Fragile X Syndrome and Autism Spectrum Disorders

Prenatal treatment with rapamycin restores enhanced hippocampal mGluR-LTD and mushroom spine size in a Down’s syndrome mouse model

Ribosome profiling in mouse hippocampus: plasticity-induced regulation and bidirectional control by TSC2 and FMRP

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