Role of mTOR in physiology and pathology of the nervous system. Biochim Biophys Acta

Laboratory of Molecular and Cellular Neurobiology, International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 02/2008; 1784(1):116-32. DOI: 10.1016/j.bbapap.2007.08.015
Source: PubMed

ABSTRACT Mammalian target of rapamycin (mTOR) is a serine-threonine protein kinase that regulates several intracellular processes in response to extracellular signals, nutrient availability, energy status of the cell and stress. mTOR regulates survival, differentiation and development of neurons. Axon growth and navigation, dendritic arborization, as well as synaptogenesis, depend on proper mTOR activity. In adult brain mTOR is crucial for synaptic plasticity, learning and memory formation, and brain control of food uptake. Recent studies reveal that mTOR activity is modified in various pathologic states of the nervous system, including brain tumors, tuberous sclerosis, cortical displasia and neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases. This review presents current knowledge about the role of mTOR in the physiology and pathology of the nervous system, with special focus on molecular targets acting downstream of mTOR that potentially contribute to neuronal development, plasticity and neuropathology.

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Available from: Malgorzata Perycz, Apr 04, 2014
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    • "c Quantification of three independent experiments as shown in b, left columns CAT-3 in total cell lysate, right columns in plasma membrane protein fraction the neuronal NO synthase (nNOS) that converts arginine to NO, display cognitive impairments, aggressivity and hyperactivity as well as additional behavioral abnormalities (Nelson et al. 1995; Weitzdoerfer et al. 2004; Tanda et al. 2009). On the other hand, arginine availability also regulates the mammalian target of rapamycin (mTOR) pathway that controls the survival, differentiation and development of neurons and synaptic plasticity, among other functions (Swiech et al. 2008); reduced CAT-3 activity would therefore be expected to have an impact on the mTOR pathway, which has previously been shown to be impaired in several forms of ASD (Bourgeron 2009; Ehninger and Silva 2011; Veenstra-VanderWeele and Blakely 2012). In particular, CAT-3 variants could modulate the effects of NMDA receptor activation on the mTOR pathway (Fig. 4) (Huang et al. 2007). "
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    ABSTRACT: Cationic amino acid transporters (CATs) mediate the entry of L-type cationic amino acids (arginine, ornithine and lysine) into the cells including neurons. CAT-3, encoded by the SLC7A3 gene on chromosome X, is one of the three CATs present in the human genome, with selective expression in brain. SLC7A3 is highly intolerant to variation in humans, as attested by the low frequency of deleterious variants in available databases, but the impact on variants in this gene in humans remains undefined. In this study, we identified a missense variant in SLC7A3, encoding the CAT-3 cationic amino acid transporter, on chromosome X by exome sequencing in two brothers with autism spectrum disorder (ASD). We then sequenced the SLC7A3 coding sequence in 148 male patients with ASD and identified three additional rare missense variants in unrelated patients. Functional analyses of the mutant transporters showed that two of the four identified variants cause severe or moderate loss of CAT-3 function due to altered protein stability or abnormal trafficking to the plasma membrane. The patient with the most deleterious SLC7A3 variant had high-functioning autism and epilepsy, and also carries a de novo 16p11.2 duplication possibly contributing to his phenotype. This study shows that rare hypomorphic variants of SLC7A3 exist in male individuals and suggest that SLC7A3 variants possibly contribute to the etiology of ASD in male subjects in association with other genetic factors.
    Amino Acids 07/2015; DOI:10.1007/s00726-015-2057-3 · 3.29 Impact Factor
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    • "ld first be needed before this could be further investigated . We found some evidence that EPSP - AP coupling was stronger in the NF1 + / − mice , but this was not observed in the CS mouse , which is like NF1 a RASopathy ( Rauen , 2013 ) . Even though many forms of intellectual disability are thought to be due to changes in synaptic transmission ( Swiech et al . , 2008 ; Stornetta and Zhu , 2011 ; Levenga and Willemsen , 2012 ) , our results thus show that changes in mTOR or Ras signaling do not result in ubiquitous in vivo changes in synaptic transmission ."
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    ABSTRACT: Defects in the rat sarcoma viral oncogene homolog (Ras)/extracellular-signal-regulated kinase and the phosphatidylinositol 3-kinase-mammalian target of rapamycin (mTOR) signaling pathways are responsible for several neurodevelopmental disorders. These disorders are an important cause for intellectual disability; additional manifestations include autism spectrum disorder, seizures, and brain malformations. Changes in synaptic function are thought to underlie the neurological conditions associated with these syndromes. We therefore studied morphology and in vivo synaptic transmission of the calyx of Held synapse, a relay synapse in the medial nucleus of the trapezoid body (MNTB) of the auditory brainstem, in mouse models of tuberous sclerosis complex (TSC), Fragile X syndrome (FXS), Neurofibromatosis type 1 (NF1), and Costello syndrome. Calyces from both Tsc1(+/-) and from Fmr1 knock-out (KO) mice showed increased volume and surface area compared to wild-type (WT) controls. In addition, in Fmr1 KO animals a larger fraction of calyces showed complex morphology. In MNTB principal neurons of Nf1 (+/) (-) mice the average delay between EPSPs and APs was slightly smaller compared to WT controls, which could indicate an increased excitability. Otherwise, no obvious changes in synaptic transmission, or short-term plasticity were observed during juxtacellular recordings in any of the four lines. Our results in these four mutants thus indicate that abnormalities of mTOR or Ras signaling do not necessarily result in changes in in vivo synaptic transmission.
    Frontiers in Cellular Neuroscience 07/2015; 9:234. DOI:10.3389/fncel.2015.00234 · 4.29 Impact Factor
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    • "One possible mechanism that may be involved in this process is the activation of the mammalian target of rapamycin (mTOR) signaling pathway which is known to mediate several cellular processes in brain, and a mTOR-mediated mechanism has been suggested to play a major role in some behavior and cognitive effects in rodents such as antidepressant-like activity (Li et al. 2010; Marsden 2012) and memory formation (Dash et al. 2006; Jobim et al. 2012). Upstream activation of mTOR through Akt is regulated by neurotrophins such as BDNF via activation of its cognate receptor TrkB (Swiech et al. 2008) which in turn regulates protein synthesis, mitochondrial function and autophagy (Wullschleger et al. 2006). "
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    ABSTRACT: Exposure to organophosphorous (OP) nerve agents such as soman inhibits the critical enzyme acetylcholinesterase (AChE) leading to excessive acetylcholine accumulation in synapses, resulting in cholinergic crisis, status epilepticus and brain damage in survivors. The hippocampus is profoundly damaged after soman exposure leading to long-term memory deficits. We have previously shown that treatment with three sequential doses of alpha-linolenic acid, an essential omega-3 polyunsaturated fatty acid, increases brain plasticity in naïve animals. However, the effects of this dosing schedule administered after a brain insult and the underlying molecular mechanisms in the hippocampus are unknown. We now show that injection of three sequential doses of alpha-linolenic acid after soman exposure increases the endogenous expression of mature BDNF, activates Akt and the mammalian target of rapamycin complex 1 (mTORC1), increases neurogenesis in the subgranular zone of the dentate gyrus, increases retention latency in the passive avoidance task and increases animal survival. In sharp contrast, while soman exposure also increases mature BDNF, this increase did not activate downstream signaling pathways or neurogenesis. Administration of the inhibitor of mTORC1, rapamycin, blocked the alpha-linolenic acid-induced neurogenesis and the enhanced retention latency but did not affect animal survival. Our results suggest that alpha-linolenic acid induces a long-lasting neurorestorative effect that involves activation of mTORC1 possibly via a BDNF-TrkB-mediated mechanism.
    Neuromolecular medicine 04/2015; 17(3). DOI:10.1007/s12017-015-8353-y · 3.68 Impact Factor
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