title: mTORC2/rictor signaling disrupts dopamine-dependent behaviors via defects in striatal dopamine neurotransmission.
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.
authors.affiliation: Vanderbilt Brain Institute, Neuroscience Program in Substance Abuse, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-8548.
authors.forename: Olga I
authors.initials: OI
authors.lastname: Dadalko
authors.affiliation: Vanderbilt Brain Institute.
authors.forename: Michael
authors.initials: M
authors.lastname: Siuta
authors.affiliation: Department of Molecular Physiology & Biophysics.
authors.forename: Amanda
authors.identifier: http://orcid.org/0000-0002-0588-658X
authors.initials: A
authors.lastname: Poe
authors.affiliation: Department of Molecular Physiology & Biophysics.
authors.forename: Kevin
authors.initials: K
authors.lastname: Erreger
authors.affiliation: Department of Molecular Physiology & Biophysics.
authors.forename: Heinrich J G
authors.initials: HJ
authors.lastname: Matthies
authors.affiliation: Department of Medicine, Tennessee Valley Healthcare System, and.
authors.forename: Kevin
authors.initials: K
authors.lastname: Niswender
authors.affiliation: Vanderbilt Brain Institute, Department of Molecular Physiology & Biophysics, Neuroscience Program in Substance Abuse, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-8548 aurelio.galli@vanderbilt.edu.
authors.forename: Aurelio
authors.initials: A
authors.lastname: Galli
mesh_terms: D000661:Amphetamine / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006220:Haloperidol / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D064231:Nestin / Q000235:genetics; D051058:Oncogene Protein v-akt / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D064231:Nestin; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C525637:rictor protein, mouse; D012694:Serine; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase; D051058:Oncogene Protein v-akt; D006220:Haloperidol; D004298:Dopamine
keywords: Akt; D2 receptor; Rictor; amphetamine; dopamine; transporter