mTORC2/rictor signaling disrupts dopamine-dependent behaviors via defects in striatal dopamine neurotransmission.

Dadalko OI, Siuta M, Poe A, Erreger K, Matthies HJ, Niswender K, Galli A
J Neurosci. 2015 35 (23): 8843-54

PMID: 26063917 · PMCID: PMC4461689 · DOI:10.1523/JNEUROSCI.0887-15.2015

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.

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MeSH Terms (22)

Amphetamine Animals Carrier Proteins Dopamine Dopamine Agents Dopamine Plasma Membrane Transport Proteins Dose-Response Relationship, Drug Gene Expression Regulation Haloperidol In Vitro Techniques Male Mice Mice, Inbred C57BL Mice, Transgenic Motor Activity Nestin Oncogene Protein v-akt Rapamycin-Insensitive Companion of mTOR Protein Serine Signal Transduction Synaptic Transmission Tyrosine 3-Monooxygenase

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