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

Dadalko, Olga I.; Siuta, Michael; Poe, Amanda; Erreger, Kevin; Matthies, Heinrich J.G.; Niswender, Kevin D.; Galli, Aurelio

doi:10.1523/jneurosci.0887-15.2015

Cited by 42 publications

(56 citation statements)

References 82 publications

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“…In line with these observations, haloperidol has been associated with rpS6 phosphorylation at Ser235/236, specifically at the level of DRD2 MSN cells in the indirect striatopallidal pathway [40]. Recently, Dadalko et al [16] demonstrated the involvement of mTORC2 signaling in the regulation of the striatal dopamine (DA) tone and D2R signaling. Additionally, they showed that the changes in striatal DA neurotransmission and associated behaviors are caused by elevated DRD2 expression.…”

Section: Discussionmentioning

confidence: 73%

“…Recently, various authors have implicated the mTOR signaling pathway in the modulation exerted by AP drugs such as thioridazine [12,13], olanzapine [14], haloperidol [15,16] and risperidone [17], among others. In parallel, several studies provide evidence for the involvement of disrupted mTOR signaling in the neuropathology of schizophrenia [18].…”

Section: Introductionmentioning

confidence: 99%

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Different Modulation of Rps6 Phosphorylation by Risperidone in Striatal Cells Sub Populations: Involvement of the mTOR Pathway in Antipsychotic-Induced Extrapyramidal Symptoms in Mice

García-Cerro¹,

Mas²,

Gortat³

et al. 2018

Neuropsychiatry

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Objective: Acute extrapyramidal symptoms (EPS) are frequent and serious adverse reactions to antipsychotic (AP) drugs. Although the proposed mechanism is an excessive blockade of dopamine D2 receptors in the striatopallidal pathway of the striatum, previous studies implicated the mTOR pathway in the susceptibility to EPS. The objective of the present study is to analyze the mTOR-mediated response to risperidone in subpopulations of striatal neurons and its relationship to risperidone-induced motor side effects. Methods:Two mouse strains (A/J and DBA/2J) with different susceptibility to developing EPS were treated with risperidone 1 mg/kg for three consecutive days. Here we monitored, by double labeling immunohistochemistry, ribosomal protein S6 (rpS6) phosphorylation (Ser235/236 and Ser244/247 sites), a marker of mTOR signaling, in the striatonigral pathway (D1-medium spiny neurons (MSNs)), the striatopallidal pathway (D2-MSNs) and striatal cholinergic interneurons. Results:We found that EPS-resistant DBA/2J mice show higher baseline levels of phosphoactivated rpS6 protein in striatal MSNs, compared with EPS-prone A/J mice. Moreover, risperidone differentially targeted rpS6 phosphorylation in direct and indirect pathway neurons in a strain-specific manner: a significant decrease in the phosphorylation of rpS6 at Ser235/236 and Ser240/244 in DRD1-MSNs EPS-resistant DBA/2J mice after; and a significant increase of phospho-Ser235/236-rpS6 in the striatopallidal pathway of the EPS-prone A/J mice in response to risperidone. Conclusions:Our results reveal the vital role of genetic background in the response to risperidone, and point to the mTOR pathway as an important factor in EPS susceptibility.

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Section: Discussionmentioning

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Different Modulation of Rps6 Phosphorylation by Risperidone in Striatal Cells Sub Populations: Involvement of the mTOR Pathway in Antipsychotic-Induced Extrapyramidal Symptoms in Mice

García-Cerro¹,

Mas²,

Gortat³

et al. 2018

Neuropsychiatry

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“…Increased mTOR signaling in the dorsal and ventral striatum could contribute to the adaptations in locomotor behavior [99] and reward pathway sensitivity [100–102] known to occur following habitual physical activity. It is somewhat surprising that exercise did not increase p-mTOR in the DMS, especially considering that exercise elicits other adaptations in this region including changes in mRNA levels of dopamine and opioid receptors [72, 103], 5-HT2C receptors [104], and increases in ΔFosB [70].…”

Section: Discussionmentioning

confidence: 99%

Exercise increases mTOR signaling in brain regions involved in cognition and emotional behavior

Lloyd

Hake

Ishiwata

et al. 2017

Behavioural Brain Research

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Exercise can enhance learning and memory and produce resistance against stress-related psychiatric disorders such as depression and anxiety. In rats, these beneficial effects of exercise occur regardless of exercise controllability: both voluntary and forced wheel running produce stress-protective effects. The mechanisms underlying these beneficial effects of exercise remain unknown. The mammalian target of rapamycin (mTOR) is a translation regulator important for cell growth, proliferation, and survival. mTOR has been implicated in enhancing learning and memory as well as antidepressant effects. Moreover, mTOR is sensitive to exercise signals such as metabolic factors. The effects of exercise on mTOR signaling, however, remain unknown. The goal of the present study was to test the hypothesis that exercise, regardless of controllability, increases levels of phosphorylated mTOR (p-mTOR) in brain regions important for learning and emotional behavior. Rats were exposed to 6 weeks of either sedentary (locked wheel), voluntary, or forced wheel running conditions. At 6 weeks, rats were sacrificed during peak running and levels of p-mTOR were measured using immunohistochemistry. Overall, both voluntary and forced exercise increased p-mTOR-positive neurons in the medial prefrontal cortex, striatum, hippocampus, hypothalamus, and amygdala compared to locked wheel controls. Exercise, regardless of controllability, also increased numbers of p-mTOR-positive glia in the striatum, hippocampus, and amygdala. For both neurons and glia, the largest increase in p-mTOR positive cells was observed after voluntary running, with forced exercise causing a more modest increase. Interestingly, voluntary exercise preferentially increased p-mTOR in astrocytes (GFAP+), while forced running increased p-mTOR in microglia (CD11+) in the inferior dentate gyrus. Results suggest that mTOR signaling is sensitive to exercise, but subtle differences exist depending on exercise controllability. Increases in mTOR signaling could contribute to the beneficial effects of exercise on cognitive function and mental health.

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“…However, the decrease in striatal ser31 TH phosphorylation in the DAT +/− and DAT −/− indicates that some DA-mediated D 2 regulation is still present, as antagonists also increase ser31 in striatum. 18 The DA D 2 receptor is coupled to ERK function, 10 and given the reported decrease in autoreceptor function in DAT +/− and DAT −/− genotypes, the decrease in ser31 TH phosphorylation, a target of ERK under depolarizing conditions, 7 would be expected. This differential response in ser31 and ser40 phosphorylation in both nucleus accumbens and striatum indicates that, under the conditions of DA neurotransmission imposed by the loss of DAT, autoreceptor-mediated control of only ser40 may be abrogated, and the segregation of phosphorylation differences in response to physiological stimuli at these two sites has been observed in other paradigms studying TH regulation in vivo .…”

Section: Discussionmentioning

confidence: 99%

Regulation of Tyrosine Hydroxylase Expression and Phosphorylation in Dopamine Transporter-Deficient Mice

Salvatore

Calipari

Jones

2016

ACS Chem. Neurosci.

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Tyrosine hydroxylase (TH) and dopamine transporters (DATs) regulate dopamine (DA) neurotransmission at the biosynthesis and reuptake steps, respectively. Dysfunction or loss of these proteins occurs in impaired locomotor or addictive behavior, but little is known about the influence of DAT expression on TH function. Differences in TH phosphorylation, DA tissue content, L-DOPA biosynthesis, and DA turnover exist between the somatodendritic and terminal field compartments of nigrostriatal and mesoaccumbens pathways. We examined whether differential DAT expression affects these compartmental differences in DA regulation by comparing TH expression and phosphorylation at ser31 and ser40. In heterozygous DAT knockout (KO) (+/−) mice, DA tissue content and DA turnover were unchanged relative to wild-type mice, despite a 40% reduction in DAT protein expression. In DAT KO (−/−) mice, DA turnover increased in all DA compartments, but DA tissue content decreased (90–96%) only in terminal fields. TH protein expression and phosphorylation were differentially affected within DA pathway compartments by relative expression of DAT. TH protein decreased (~74%), though to a significantly lesser extent than DA, in striatum and nucleus accumbens (NAc) in DAT −/− mice, with no decrease in substantia nigra or ventral tegmental area. Striatal ser31 TH phosphorylation and recovery of DA relative to TH protein expression in DAT +/− and DAT −/− mice decreased, whereas ser40 TH phosphorylation increased ~2- to 3-fold in striatum and NAc of DAT −/− mice. These results suggest that DAT expression affects TH expression and phosphorylation largely in DA terminal field compartments, further corroborating evidence for dichotomous regulation of TH between somatodendritic and terminal field compartments of the nigrostriatal and mesoaccumbens pathways.

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

Cited by 42 publications

References 82 publications

Different Modulation of Rps6 Phosphorylation by Risperidone in Striatal Cells Sub Populations: Involvement of the mTOR Pathway in Antipsychotic-Induced Extrapyramidal Symptoms in Mice

Different Modulation of Rps6 Phosphorylation by Risperidone in Striatal Cells Sub Populations: Involvement of the mTOR Pathway in Antipsychotic-Induced Extrapyramidal Symptoms in Mice

Exercise increases mTOR signaling in brain regions involved in cognition and emotional behavior

Regulation of Tyrosine Hydroxylase Expression and Phosphorylation in Dopamine Transporter-Deficient Mice

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