Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the October 6th issue of Science, Raab-Graham et al. described two surprising findings. They discovered that local dendritic translation of Kv1.1 occurs in CA1 dendrites of rat hippocampal slices and in cultured neurons. This local translation is inhibited by NMDA receptor-mediated synaptic signaling acting through the mTOR kinase.
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PMID:Kv1.1 takes a deTOR from the axon to the dendrite. 1708 6

Protein synthesis is required for persistent forms of synaptic plasticity, including long-term potentiation (LTP). A key regulator of LTP-related protein synthesis is mammalian target of rapamycin (mTOR), which is thought to modulate translational capacity by facilitating the synthesis of particular components of the protein synthesis machinery. Recently, extracellularly regulated kinase (ERK) also was shown to mediate plasticity-related translation, an effect that may involve regulation of the mTOR pathway. We studied the interaction between the mTOR and ERK pathways in hippocampal LTP induced at CA3-CA1 synapses by high-frequency synaptic stimulation (HFS). Within minutes after HFS, the expression of multiple translational proteins, the synthesis of which is under the control of mTOR, increased in area CA1 stratum radiatum. This upregulation was detected in pyramidal cell dendrites and was blocked by inhibitors of the ERK pathway. In addition, ERK mediated the stimulation of mTOR by HFS. The possibility that ERK regulates mTOR by acting at a component further upstream in the phosphatidylinositide 3-kinase (PI3K)-mTOR pathway was tested by probing the phosphorylation of p90-S6 kinase, phosphoinositide-dependent kinase 1 (PDK1), and Akt. ERK inhibitors blocked HFS-induced phosphorylation of all three proteins at sites implicated in the regulation of mTOR. Moreover, a component of basal and HFS-induced ERK activity depended on PI3K, indicating that mTOR-mediated protein synthesis in LTP requires coincident and mutually dependent activity in the PI3K and ERK pathways. The role of ERK in regulating PDK1 and Akt, with their extensive effects on cellular function, has important implications for the coordinated response of the neuron to LTP-inducing stimulation.
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PMID:Mitogen-activated protein kinase upregulates the dendritic translation machinery in long-term potentiation by controlling the mammalian target of rapamycin pathway. 1753 59

Gq-coupled, M1 muscarinic acetylcholine receptors (mAChRs) facilitate hippocampal learning, memory, and synaptic plasticity. M1 mAChRs induce long-term synaptic depression (LTD), but little is known about the underlying mechanisms of mAChR-dependent LTD and its link to cognitive function. Here, we demonstrate that chemical activation of M1 mAChRs induces LTD in hippocampal area CA1, which relies on rapid protein synthesis, as well as the extracellular signal-regulated kinase and mammalian target of rapamycin translational activation pathways. Synaptic stimulation of M1 mAChRs, alone, or together with the Gq-coupled glutamate receptors (mGluRs), also results in protein synthesis-dependent LTD. New proteins maintain mAChR-dependent LTD through a persistent decrease in surface AMPA receptors. mAChRs stimulate translation of the RNA-binding protein, Fragile X mental retardation protein (FMRP) and FMRP target mRNAs. In mice without FMRP (Fmr1 knock-out), a model for human Fragile X syndrome mental retardation (FXS), both mGluR- and mAChR-dependent protein synthesis and LTD are affected. Our results reveal that multiple Gq-coupled receptors converge on a common protein synthesis-dependent LTD mechanism, which is aberrant in FXS. These findings suggest novel therapeutic strategies for FXS in the form of mAChR antagonists.
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PMID:Multiple Gq-coupled receptors converge on a common protein synthesis-dependent long-term depression that is affected in fragile X syndrome mental retardation. 1795 5

Evidence indicates that activation of the neuronal protein synthesis machinery is required in areas of the brain relevant to memory for consolidation and persistence of the mnemonic trace. Here, we report that inhibition of hippocampal mTOR, a protein kinase involved in the initiation of mRNA translation, immediately or 180min but not 540min after training impairs consolidation of long-term object recognition memory without affecting short-term memory retention or exploratory behavior. When infused into dorsal CA1 after long-term memory reactivation in the presence of familiar objects the mTOR inhibitor rapamycin (RAP) did not affect retention. However, when given immediately after exposing animals to a novel and a familiar object, RAP impaired memory for both of them. The amnesic effect of the post-retrieval administration of RAP was long-lasting, did not happen after exposure to two novel objects or following exploration of the training arena in the absence of other stimuli, suggesting that it was contingent with reactivation of the consolidated trace in the presence of a behaviorally relevant and novel cue. Our results indicate that mTOR activity is required in the dorsal hippocampus for consolidation of object recognition memory and suggest that inhibition of this kinase after memory retrieval in the presence of a particular set of cues hinders persistence of the original recognition memory trace.
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PMID:On the participation of mTOR in recognition memory. 1803 84

Stress dramatically affects the induction of hippocampal synaptic plasticity; however, the molecular details of how it does so remain unclear. Phosphatidylinositol 3-kinase (PI3K) signaling plays a crucial role in promoting neuronal survival and neuroplasticity, but its role, if any, in stress-induced alterations of long term potentiation (LTP) and long term depression (LTD) is unknown. We found here that inhibitors of PI3K signaling blocked the effects of acute restraint-tail shock stress protocol on LTP and LTD. Therefore, the purpose of the present study is to explore the signaling events involving PI3K in terms of its role in mediating stress protocol-induced alterations of LTP and LTD. We found that stress protocol-induced PI3K activation can be blocked by various inhibitors, including RU38486 for glucocorticoid receptors, LY294002 for PI3K, and dl-2-amino-5-phosphonopentanoic acid for N-methyl-D-aspartate receptors or brain-derived neurotrophic factor antisense oligonucleotides. Also, immunoblotting analyses revealed that stress protocol induced a profound and prolonged phosphorylation of numbers of PI3K downstream effectors, including 3-phosphoinositide-dependent protein kinase-1, protein kinase B, mammalian target of rapamycin (mTOR), p70 S6 kinase, and eukaryotic initiation factor 4B in hippocampal CA1 homogenate, which was prevented by the PI3K inhibitor pretreatment. More importantly, we found that stress protocol significantly increased the protein expression of dendritic scaffolding protein PSD-95 (postsynaptic density-95), which is known to be involved in LTP and LTD, in an mTOR-dependent manner. These results identify a key role of PI3K signaling in mediating the stress protocol-induced modification of hippocampal synaptic plasticity and further suggest that PI3K may do so by invoking the protein expression of PSD-95.
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PMID:Phosphatidylinositol 3-kinase activation is required for stress protocol-induced modification of hippocampal synaptic plasticity. 1805 5

Group I metabotropic glutamate receptors (mGluRs) induce a form of long-term synaptic depression (mGluR-LTD) in area CA1 of the hippocampus that requires rapid protein synthesis. Although much is known about the mechanisms underlying mGluR-LTD, it is unclear how mGluRs couple to the effectors necessary for translation initiation. A clue comes from work in the mouse model of Fragile X syndrome [Fmr1 knock-out (KO) mice], where group 1 mGluR stimulation of protein synthesis is absent and mGluRs are less associated with the postsynaptic scaffolding protein Homer (Giuffrida et al., 2005). Here, we examined the role of Homer interactions in mGluR-LTD and mGluR signaling to protein synthesis machinery in wild-type and Fmr1 KO animals. A peptide that mimics the C-terminal tail of mGluR5 (mGluR5ct), shown previously to disrupt Homer interactions with mGluRs, blocks mGluR-LTD and mGluR-signaling to protein synthesis initiation in wild-type animals. Disruption of mGluR-Homer interactions selectively blocks mGluR activation of the phosphoinositide 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR), but not ERK (extracellular signal-regulated kinase), pathway and translation of a 5' terminal oligopyrimidine tract containing mRNA, Elongation factor 1alpha. In Fmr1 KO mice, mGluR-LTD is insensitive to disruption of Homer interactions and mGluR activation of PI3K-mTOR is lost. Our results find specific roles for Homer in mGluR signaling and plasticity and suggest that reduced mGluR-Homer interactions in Fmr1 KO mice lead to a deficit in mGluR stimulation of translation initiation.
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PMID:Homer interactions are necessary for metabotropic glutamate receptor-induced long-term depression and translational activation. 1818 96

The late phase of long-term potentiation (LTP) requires activation of the mammalian target of rapamycin (mTOR) pathway and synthesis of new proteins. mTOR regulates protein synthesis via phosphorylation of 4E-binding proteins (4E-BPs) and S6K, and via selective up-regulation of 5' terminal oligopyrimidine (5' TOP) mRNAs that encode components of the translational machinery. In this study, we explored the regulation of 5' TOP mRNAs during late-LTP (L-LTP). Synaptic plasticity was studied at Schaffer collateral--CA1 pyramidal cell synapses in rat organotypic hippocampal slices. Forskolin, an adenylate cyclase activator, induced L-LTP in organotypic slices that was mTOR-dependent. To determine if 5' TOP mRNAs are specifically up-regulated during L-LTP, we generated a 5' TOP-myr-dYFP reporter to selectively monitor 5' TOP translation. Confocal imaging experiments in cultured slices revealed an increase in somatic and dendritic fluorescence after forskolin treatment. This up-regulation was dependent on an intact TOP sequence and was mTOR, extracellular signal-regulated kinase (ERK), and phosphatidylinositol 3-kinase (PI3K)-dependent. Our findings indicate that forskolin induces L-LTP in hippocampal neurons and up-regulates 5' TOP mRNAs translation via mTOR, suggesting that up-regulation of the translational machinery is a candidate mechanism for the stabilization of LTP.
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PMID:Forskolin induction of late-LTP and up-regulation of 5' TOP mRNAs translation via mTOR, ERK, and PI3K in hippocampal pyramidal cells. 1846 37

Tuberous sclerosis is a single-gene disorder caused by heterozygous mutations in the TSC1 (9q34) or TSC2 (16p13.3) gene and is frequently associated with mental retardation, autism and epilepsy. Even individuals with tuberous sclerosis and a normal intelligence quotient (approximately 50%) are commonly affected with specific neuropsychological problems, including long-term and working memory deficits. Here we report that mice with a heterozygous, inactivating mutation in the Tsc2 gene (Tsc2(+/-) mice) show deficits in learning and memory. Cognitive deficits in Tsc2(+/-) mice emerged in the absence of neuropathology and seizures, demonstrating that other disease mechanisms are involved. We show that hyperactive hippocampal mammalian target of rapamycin (mTOR) signaling led to abnormal long-term potentiation in the CA1 region of the hippocampus and consequently to deficits in hippocampal-dependent learning. These deficits included impairments in two spatial learning tasks and in contextual discrimination. Notably, we show that a brief treatment with the mTOR inhibitor rapamycin in adult mice rescues not only the synaptic plasticity, but also the behavioral deficits in this animal model of tuberous sclerosis. The results presented here reveal a biological basis for some of the cognitive deficits associated with tuberous sclerosis, and they show that treatment with mTOR antagonists ameliorates cognitive dysfunction in a mouse model of this disorder.
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PMID:Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis. 1856 33

Adult neurogenesis persists in the subventricular zone and the dentate gyrus and can be induced upon central nervous system injury. However, the final contribution of newborn neurons to neuronal networks is limited. Here we show that in neural stem cells, stimulation of the "death receptor" CD95 does not trigger apoptosis but unexpectedly leads to increased stem cell survival and neuronal specification. These effects are mediated via activation of the Src/PI3K/AKT/mTOR signaling pathway, ultimately leading to a global increase in protein translation. Induction of neurogenesis by CD95 was further confirmed in the ischemic CA1 region, in the naive dentate gyrus, and after forced expression of CD95L in the adult subventricular zone. Lack of hippocampal CD95 resulted in a reduction in neurogenesis and working memory deficits. Following global ischemia, CD95-mediated brain repair rescued behavioral impairment. Thus, we identify the CD95/CD95L system as an instructive signal for ongoing and injury-induced neurogenesis.
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PMID:The death receptor CD95 activates adult neural stem cells for working memory formation and brain repair. 1966 83

Fragile X syndrome, the most common form of inherited mental retardation and leading genetic cause of autism, is caused by transcriptional silencing of the Fmr1 gene. The fragile X mental retardation protein (FMRP), the gene product of Fmr1, is an RNA binding protein that negatively regulates translation in neurons. The Fmr1 knock-out mouse, a model of fragile X syndrome, exhibits cognitive deficits and exaggerated metabotropic glutamate receptor (mGluR)-dependent long-term depression at CA1 synapses. However, the molecular mechanisms that link loss of function of FMRP to aberrant synaptic plasticity remain unclear. The mammalian target of rapamycin (mTOR) signaling cascade controls initiation of cap-dependent translation and is under control of mGluRs. Here we show that mTOR phosphorylation and activity are elevated in hippocampus of juvenile Fmr1 knock-out mice by four functional readouts: (1) association of mTOR with regulatory associated protein of mTOR; (2) mTOR kinase activity; (3) phosphorylation of mTOR downstream targets S6 kinase and 4E-binding protein; and (4) formation of eukaryotic initiation factor complex 4F, a critical first step in cap-dependent translation. Consistent with this, mGluR long-term depression at CA1 synapses of FMRP-deficient mice is exaggerated and rapamycin insensitive. We further show that the p110 subunit of the upstream kinase phosphatidylinositol 3-kinase (PI3K) and its upstream activator PI3K enhancer PIKE, predicted targets of FMRP, are upregulated in knock-out mice. Elevated mTOR signaling may provide a functional link between overactivation of group I mGluRs and aberrant synaptic plasticity in the fragile X mouse, mechanisms relevant to impaired cognition in fragile X syndrome.
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PMID:Dysregulation of mTOR signaling in fragile X syndrome. 2050 79


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