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Articles, Cellular/Molecular

mTORC2/Rictor Signaling Disrupts Dopamine-Dependent Behaviors via Defects in Striatal Dopamine Neurotransmission

Olga I. Dadalko, Michael Siuta, Amanda Poe, Kevin Erreger, Heinrich J.G. Matthies, Kevin Niswender and Aurelio Galli
Journal of Neuroscience 10 June 2015, 35 (23) 8843-8854; DOI: https://doi.org/10.1523/JNEUROSCI.0887-15.2015
Olga I. Dadalko
1Vanderbilt Brain Institute,
5Neuroscience Program in Substance Abuse, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-8548
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Michael Siuta
1Vanderbilt Brain Institute,
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Amanda Poe
2Department of Molecular Physiology & Biophysics,
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Kevin Erreger
2Department of Molecular Physiology & Biophysics,
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Heinrich J.G. Matthies
2Department of Molecular Physiology & Biophysics,
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Kevin Niswender
3Department of Medicine,
4Tennessee Valley Healthcare System, and
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Aurelio Galli
1Vanderbilt Brain Institute,
2Department of Molecular Physiology & Biophysics,
5Neuroscience Program in Substance Abuse, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-8548
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Abstract

Disrupted neuronal protein kinase B (Akt) signaling has been associated with dopamine (DA)-related neuropsychiatric disorders, including schizophrenia, a devastating mental illness. We hypothesize that proper DA neurotransmission is therefore dependent upon intact neuronal Akt function. Akt is activated by phosphorylation of two key residues: Thr308 and Ser473. Blunted Akt phosphorylation at Ser473 (pAkt-473) has been observed in lymphocytes and postmortem brains of schizophrenia patients, and psychosis-prone normal individuals. Mammalian target of rapamycin (mTOR) complex 2 (mTORC2) is a multiprotein complex that is responsible for phosphorylation of Akt at Ser473 (pAkt-473). We demonstrate that mice with disrupted mTORC2 signaling in brain exhibit altered striatal DA-dependent behaviors, such as increased basal locomotion, stereotypic counts, and exaggerated response to the psychomotor effects of amphetamine (AMPH). Combining in vivo and ex vivo pharmacological, electrophysiological, and biochemical techniques, we demonstrate that the changes in striatal DA neurotransmission and associated behaviors are caused, at least in part, by elevated D2 DA receptor (D2R) expression and upregulated ERK1/2 activation. Haloperidol, a typical antipsychotic and D2R blocker, reduced AMPH hypersensitivity and elevated pERK1/2 to the levels of control animals. By viral gene delivery, we downregulated mTORC2 solely in the dorsal striatum of adult wild-type mice, demonstrating that striatal mTORC2 regulates AMPH-stimulated behaviors. Our findings implicate mTORC2 signaling as a novel pathway regulating striatal DA tone and D2R signaling.

  • Akt
  • amphetamine
  • D2 receptor
  • dopamine
  • Rictor
  • transporter
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The Journal of Neuroscience: 35 (23)
Journal of Neuroscience
Vol. 35, Issue 23
10 Jun 2015
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mTORC2/Rictor Signaling Disrupts Dopamine-Dependent Behaviors via Defects in Striatal Dopamine Neurotransmission
Olga I. Dadalko, Michael Siuta, Amanda Poe, Kevin Erreger, Heinrich J.G. Matthies, Kevin Niswender, Aurelio Galli
Journal of Neuroscience 10 June 2015, 35 (23) 8843-8854; DOI: 10.1523/JNEUROSCI.0887-15.2015

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mTORC2/Rictor Signaling Disrupts Dopamine-Dependent Behaviors via Defects in Striatal Dopamine Neurotransmission
Olga I. Dadalko, Michael Siuta, Amanda Poe, Kevin Erreger, Heinrich J.G. Matthies, Kevin Niswender, Aurelio Galli
Journal of Neuroscience 10 June 2015, 35 (23) 8843-8854; DOI: 10.1523/JNEUROSCI.0887-15.2015
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Keywords

  • Akt
  • amphetamine
  • D2 receptor
  • dopamine
  • Rictor
  • transporter

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