Dysregulation of the Norepinephrine Transporter Sustains Cortical Hypodopaminergia and Schizophrenia-Like Behaviors in Neuronal Rictor Null Mice

Siuta, Michael; Robertson, Sabrina D.; Kocalis, Heidi; Saunders, Christine; Gresch, Paul J.; Khatri, Vivek; Shiota, Chiyo; Kennedy, Jack P; Lindsley, Craig W.; Daws, Lynette C.; Polley, Daniel B.; Veenstra‐VanderWeele, Jeremy; Stanwood, Gregg D.; Magnuson, Mark A.; Niswender, Kevin D.; Galli, Aurelio

doi:10.1371/journal.pbio.1000393

Cited by 85 publications

(106 citation statements)

References 49 publications

(78 reference statements)

Supporting

Mentioning

101

Contrasting

Order By: Relevance

“…Furthermore, noradrenergic depletion of PFC attenuates cocaine CPP (64). At the transporter level, NET mediates DA clearance in the PFC (3)(4)(5)(6)(7)(8), underscoring the importance of NET function in controlling DA signaling. Thus, our finding that p38 MAPK inhibition or NET-Thr 30 intervention can attenuate cocaine CPP indicates a role for NET regulation in the PFC and in cocaine-reinforcing effects.…”

Section: Discussionmentioning

confidence: 99%

“…(error bars). * indicates a significant change from vehicle control (one-way analysis of variance; Dunnett's test: F (4,8) ϭ 31.67 for TAT-NET-Thr 30 and F (4,8) ϭ 23.00 for TAT-NET-T30A, p Ͻ 0.05). TH immunoblots corresponding to total are shown for equal protein loading.…”

Section: Discussionmentioning

confidence: 99%

“…(error bars). * indicates a significant change from vehicle control (one-way analysis of variance; Dunnett's test: F (4,8) cocaine challenge produced significant locomotor sensitization in mice that were injected with vehicle prior to cocaine challenge (Fig. 3A).…”

Section: Cocaine-induced Net Up-regulation and Phosphorylationmentioning

confidence: 99%

“…(error bars). * indicates a significant change from vehicle control (one-way analysis of variance; Dunnett's test: F (4,8) Synaptosomes treated as indicated were solubilized, and equal aliquots of synaptosome extracts were subjected to pulldown experiment using phospho-p38 MAPK (p-p38MAPK) antibody-immobilized beads or immunoprecipitation with NET antibody followed by SDS-PAGE and immunoblotted with NET, DAT, SERT, or phospho-or total p38 MAPK antibodies. Representative NET-, DAT-, SERT-, and total or phospho-p38 MAPK-immunoreactive bands from two independent experiments are shown.…”

Section: Cocaine-induced Net Up-regulation and Phosphorylationmentioning

confidence: 99%

See 3 more Smart Citations

A Role for p38 Mitogen-activated Protein Kinase-mediated Threonine 30-dependent Norepinephrine Transporter Regulation in Cocaine Sensitization and Conditioned Place Preference

Padmanabhan

Kamalakkannan

Damaj

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Cocaine-activated p38 MAPK-mediated norepinephrine transporter (NET) threonine 30 phosphorylation up-regulates NET. Results: p38 MAPK inhibition and TAT-NET-Thr 30 peptide blocks cocaine-mediated NET up-regulation and cocaine-induced locomotor sensitization and conditioned place preference (CPP). Conclusion: Blockade of p38 MAPK-mediated Thr30 -dependent NET regulation attenuates cocaine-induced locomotor sensitization, CPP, and CPP reinstatement. Significance: Regulation of NET plays a mechanistic role in cocaine-mediated behaviors.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Cocaine-induced Net Up-regulation and Phosphorylationmentioning

confidence: 99%

Section: Cocaine-induced Net Up-regulation and Phosphorylationmentioning

confidence: 99%

See 2 more Smart Citations

A Role for p38 Mitogen-activated Protein Kinase-mediated Threonine 30-dependent Norepinephrine Transporter Regulation in Cocaine Sensitization and Conditioned Place Preference

Padmanabhan

Kamalakkannan

Damaj

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…The dominant social paradigm in mice focuses on time spent exploring a novel mouse (Silverman et al, 2010), which is quite different than our complex assessment of social behavior in a human child (Lord et al, 2000). Without verbal communication, investigators define 'schizophrenialike' behavior in mice using surrogate measures like prepulse inhibition or response to a psychotomimetic drug (Siuta et al, 2010). From a cognitive perspective, mice would perform at the floor (or sub-floor) of human intelligence testing.…”

Section: Utility Of Rodent Models: Mice Are Not Little Humansmentioning

confidence: 99%

Intervention in the Context of Development: Pathways Toward New Treatments

Veenstra‐VanderWeele

Warren

2014

Neuropsychopharmacol

Self Cite

View full text Add to dashboard Cite

Neuropsychiatric disorders vary substantially in age of onset but are best understood within the context of neurodevelopment. Here, we review opportunities for intervention at critical points in developmental trajectories. We begin by discussing potential opportunities to prevent neuropsychiatric disorders. Once symptoms begin to emerge, a number of interventions have been studied either before a diagnosis can be made or shortly after diagnosis. Although some of these interventions are helpful, few are based upon an understanding of pathophysiology, and most ameliorate rather than resolve symptoms. As such, in the next portion of the review, we turn our discussion to genetic syndromes that are rare phenocopies of common diagnoses such as autism spectrum disorder or schizophrenia. Cellular or animal models of these syndromes point to specific regulatory or signaling pathways. As examples, findings from the mouse models of Fragile X and Rett syndromes point to potential treatments now being tested in randomized clinical trials. Paralleling oncology, we can hope that our treatments will move from nonspecific, like chemotherapies thrown at a wide range of tumor types, to specific, like the protein kinase inhibitors that target molecularly defined tumors. Some of these targeted treatments later show benefit for a broader, yet specific, array of cancers. We can hope that medications developed within rare neurodevelopmental syndromes will similarly help subgroups of patients with disruptions in overlapping signaling pathways. The insights gleaned from treatment development in rare phenocopy syndromes may also teach us how to test treatments based upon emerging common genetic or environmental risk factors.

show abstract

Genetic association of ACSM1 variation with schizophrenia and major depressive disorder in the Han Chinese population

et al. 2015

American J of Med Genetics Pt B

View full text Add to dashboard Cite

Schizophrenia (SCZ) and major depressive disorder (MDD) are two of the most common and severe mental disorders, the etiologies of which are not yet clearly elucidated. The ACSM1 gene has been identified as a susceptibility gene for SCZ in two previous genome-wide association studies (GWAS). ACSM1 catalyzes the activation of fatty acids and plays an important role in the metabolic system. Some evidence has suggested that ACSM1 contributes to a genetic risk for MDD. The present study aimed to evaluate the common genetic risk of the ACSM1 gene in these two disorders in the Han Chinese population. In total, 1235 patients with SCZ, 1045 patients with MDD and 1235 control subjects of Chinese origin were recruited. Six single nuclear polymorphisms (SNPs) in ACSM1 were genotyped to test their associations with SCZ and MDD. SNP rs163234 was found to be significantly associated with both SCZ (permutated Pallele=1.700×10(-3), OR=1.350 [95% CI=1.152-1.581]) and MDD (permutated Pallele=4.800×10(-3), OR=1.329 [95% CI=1.127-1.567]). SNP rs433598 showed a strong association with SCZ (permutated Pallele=4.300×10(-3), OR=1.303 [95% CI=1.117-1.520]). Haplotype analysis of the blocks containing the two positive markers also revealed a significant association. This is the first study to assess the possible association of the ACSM1 gene with a genetic susceptibility for MDD. Our data are the first to suggest a positive association of the ACSM1 gene with a genetic susceptibility for SCZ and MDD in the Han Chinese population.

show abstract

Dysregulation of the Norepinephrine Transporter Sustains Cortical Hypodopaminergia and Schizophrenia-Like Behaviors in Neuronal Rictor Null Mice

Abstract: A novel animal model highlights the link between Akt dysfunction, reduced cortical dopamine function, norepinephrine transporters, and schizophrenia-like behaviors.

Cited by 85 publications

References 49 publications

A Role for p38 Mitogen-activated Protein Kinase-mediated Threonine 30-dependent Norepinephrine Transporter Regulation in Cocaine Sensitization and Conditioned Place Preference

A Role for p38 Mitogen-activated Protein Kinase-mediated Threonine 30-dependent Norepinephrine Transporter Regulation in Cocaine Sensitization and Conditioned Place Preference

Intervention in the Context of Development: Pathways Toward New Treatments

Genetic association of ACSM1 variation with schizophrenia and major depressive disorder in the Han Chinese population

Contact Info

Product

Resources

About