Siuta MA, Robertson SD, Kocalis H, Saunders C, Gresch PJ, Khatri V et al. Dysregulation of the norepinephrine transporter sustains cortical hypodopaminergia and schizophrenia-like behaviors in neuronal rictor null mice. PLoS Biol 8: e1000393

Center for Molecular Neuroscience, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
PLoS Biology (Impact Factor: 9.34). 06/2010; 8(6):e1000393. DOI: 10.1371/journal.pbio.1000393
Source: PubMed


The mammalian target of rapamycin (mTOR) complex 2 (mTORC2) is a multimeric signaling unit that phosphorylates protein kinase B/Akt following hormonal and growth factor stimulation. Defective Akt phosphorylation at the mTORC2-catalyzed Ser473 site has been linked to schizophrenia. While human imaging and animal studies implicate a fundamental role for Akt signaling in prefrontal dopaminergic networks, the molecular mechanisms linking Akt phosphorylation to specific schizophrenia-related neurotransmission abnormalities have not yet been described. Importantly, current understanding of schizophrenia suggests that cortical decreases in DA neurotransmission and content, defined here as cortical hypodopaminergia, contribute to both the cognitive deficits and the negative symptoms characteristic of this disorder. We sought to identify a mechanism linking aberrant Akt signaling to these hallmarks of schizophrenia. We used conditional gene targeting in mice to eliminate the mTORC2 regulatory protein rictor in neurons, leading to impairments in neuronal Akt Ser473 phosphorylation. Rictor-null (KO) mice exhibit prepulse inhibition (PPI) deficits, a schizophrenia-associated behavior. In addition, they show reduced prefrontal dopamine (DA) content, elevated cortical norepinephrine (NE), unaltered cortical serotonin (5-HT), and enhanced expression of the NE transporter (NET). In the cortex, NET takes up both extracellular NE and DA. Thus, we propose that amplified NET function in rictor KO mice enhances accumulation of both NE and DA within the noradrenergic neuron. This phenomenon leads to conversion of DA to NE and ultimately supports both increased NE tissue content as well as a decrease in DA. In support of this hypothesis, NET blockade in rictor KO mice reversed cortical deficits in DA content and PPI, suggesting that dysregulation of DA homeostasis is driven by alteration in NET expression, which we show is ultimately influenced by Akt phosphorylation status. These data illuminate a molecular link, Akt regulation of NET, between the recognized association of Akt signaling deficits in schizophrenia with a specific mechanism for cortical hypodopaminergia and hypofunction. Additionally, our findings identify Akt as a novel modulator of monoamine homeostasis in the cortex.

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    • "Review with schizophrenia (Emamian et al., 2004). Along these lines, a brain-specific Rictor knockout showed a reduction in dopamine in the prefrontal cortex, elevated expression of norepinephrine transporter, and deficits in prepulse inhibition, a schizophreniaassociated endophenotype (Siuta et al., 2010). Thus, an increase in mTORC1 signaling secondary to suppression of DISC1 or a decrease in mTORC2 signaling secondary to loss of Rictor or AKT1 signaling may contribute to schizophrenia-like phenotypes in rodents. "
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    ABSTRACT: The mechanistic target of rapamycin (mTOR) signaling pathway is a crucial cellular signaling hub that, like the nervous system itself, integrates internal and external cues to elicit critical outputs including growth control, protein synthesis, gene expression, and metabolic balance. The importance of mTOR signaling to brain function is underscored by the myriad disorders in which mTOR pathway dysfunction is implicated, such as autism, epilepsy, and neurodegenerative disorders. Pharmacological manipulation of mTOR signaling holds therapeutic promise and has entered clinical trials for several disorders. Here, we review the functions of mTOR signaling in the normal and pathological brain, highlighting ongoing efforts to translate our understanding of cellular physiology into direct medical benefit for neurological disorders.
    Neuron 10/2014; 84(2):275-291. DOI:10.1016/j.neuron.2014.09.034 · 15.05 Impact Factor
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    • "Neuronal Rictor knockout mice have been described previously [39]. Briefly, Rictorflox/flox mice [37] were crossed with neuronal nestin Cre (Nes-Cre) +/+ mice [41] resulting in F1 generation offspring of the genotype Nes-Cre+/−; Rictor flox/WT (where WT is wild type). "
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    ABSTRACT: Insulin signaling in the central nervous system (CNS) regulates energy balance and peripheral glucose homeostasis. Rictor is a key regulatory/structural subunit of the mTORC2 complex and is required for hydrophobic motif site phosphorylation of Akt at serine 473. To examine the contribution of neuronal Rictor/mTORC2 signaling to CNS regulation of energy and glucose homeostasis, we utilized Cre-LoxP technology to generate mice lacking Rictor in all neurons, or in either POMC or AgRP expressing neurons. Rictor deletion in all neurons led to increased fat mass and adiposity, glucose intolerance and behavioral leptin resistance. Disrupting Rictor in POMC neurons also caused obesity and hyperphagia, fasting hyperglycemia and pronounced glucose intolerance. AgRP neuron specific deletion did not impact energy balance but led to mild glucose intolerance. Collectively, we show that Rictor/mTORC2 signaling, especially in POMC-expressing neurons, is important for central regulation of energy and glucose homeostasis.
    Molecular Metabolism 07/2014; 3(4). DOI:10.1016/j.molmet.2014.01.014
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    • ") mice have been created to establish conditional knockouts to study the selective loss of mTOR or of each complex in different tissues and cell types. Studies using these mouse lines are rapidly emerging and include loss of mTOR in muscle (Risson et al., 2009; Lang et al., 2010) or Schwann cells (Sherman et al., 2012), of raptor in liver (Sengupta et al., 2010), thymocytes (Tang et al., 2012) or the haematopoietic lineage (Hoshii et al., 2012; Kalaitzidis et al., 2012) and of rictor in muscle (Kumar et al., 2008), prostate (Guertin et al., 2009), fat (Kumar et al., 2010), neurons (Siuta et al., 2010), beta cells (Gu et al., 2010), T-cells/thymocytes (Lee et al., 2010; Tang et al., 2012), liver (Yuan et al., 2012), the haematopoietic lineage (Kalaitzidis et al., 2012) or neural progenitor cells (Carson et al., 2013). These studies demonstrate the wide importance for the mTOR complexes in many cell systems. "
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    ABSTRACT: Oligodendrocyte development is controlled by numerous extracellular signals that regulate a series of transcription factors that promote the differentiation of oligodendrocyte progenitor cells to myelinating cells in the central nervous system. A major element of this regulatory system that has only recently been studied is the intracellular signaling from surface receptors to transcription factors to downregulate inhibitors and upregulate inducers of oligodendrocyte differentiation and myelination. The current review focuses on one such pathway: the mammalian target of rapamycin (mTOR) pathway, which integrates signals in many cell systems and induces cell responses including cell proliferation and cell differentiation. This review describes the known functions of mTOR as they relate to oligodendrocyte development, and its recently discovered impact on oligodendrocyte differentiation and myelination. A potential model for its role in oligodendrocyte development is proposed.
    ASN Neuro 02/2013; 5(1). DOI:10.1042/AN20120092 · 4.02 Impact Factor
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