High dopamine turnover in the brains of Sandy mice

Murotani, Tomotaka; Ishizuka, Tomoko; Hattori, Satoko; Hashimoto, Ryota; Matsuzaki, Shinsuke; Yamatodani, Atsushi

doi:10.1016/j.neulet.2007.05.019

Cited by 54 publications

(32 citation statements)

References 29 publications

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“…The putative increase in dopamine turnover in the sandy mouse (Murotani et al, 2007) presumably caused by increased dopamine transmission, would be consistent with DTNBP1 siRNA experiments on PC12 cells (Kumamoto et al, 2006). Presynaptic DRD2 can function as an autoreceptor, which allows an inhibitory feedback mechanism by altering dopamine synthesis, release, and reuptake in response to increased synaptic dopamine.…”

Section: Discussionsupporting

confidence: 75%

“…In rat pheochromocytoma cell line (PC12) cells, siRNA induced downregulation of dysbindin increased dopamine (DA) release (Kumamoto et al, 2006). This may be physiologically relevant, because the cortex of the dysbindin mutant mouse (sandy, sdy) appears to have decreased dopamine levels (Murotani et al, 2007), perhaps from increased dopaminergic transmission and turnover.…”

Section: Introductionmentioning

confidence: 99%

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Evidence That the BLOC-1 Protein Dysbindin Modulates Dopamine D₂Receptor Internalization and Signaling But Not D₁Internalization

Iizuka¹,

Sei²,

Weinberger³

et al. 2007

J. Neurosci.

120

109

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The schizophrenia susceptibility gene dystrobrevin-binding protein 1 (DTNBP1) encodes dysbindin, which along with its binding partner Muted is an essential component of the biogenesis of lysosome-related organelles complex 1 (BLOC-1). Dysbindin expression is reduced in schizophrenic brain tissue, but the molecular mechanisms by which this contributes to pathogenesis and symptomatology are unknown. We studied the effects of transfection of DTNBP1 siRNA on cell surface levels of dopamine D 2 receptor (DRD2) in human SH-SY5Y neuroblastoma cells and in rat primary cortical neurons. DTNBP1 siRNA decreased dysbindin protein, increased cell surface DRD2 and blocked dopamine-induced DRD2 internalization. MUTED siRNA produced similar effects. In contrast, decreased dysbindin did not change dopamine D 1 receptor (DRD1) levels, or its basal or dopamine-induced internalization. The DRD2 agonist quinpirole reduced phosphorylation of CREB (cAMP response element-binding protein) in dysbindin downregulated cells, demonstrating enhanced intracellular signaling caused by the upregulation of DRD2. This is the first demonstration of a schizophrenia susceptibility gene exerting a functional effect on DRD2 signaling, a pathway that has long been implicated in the illness. We propose a molecular mechanism for pathogenesis in which risk alleles in DTNBP1, or other factors that also downregulate dysbindin, compromise the ability of BLOC-1 to traffic DRD2 toward degradation, but has little effect on DRD1 trafficking. Impaired trafficking of DRD2 decreases dopamine-induced internalization, and with more receptors retained on the cell surface, dopamine stimulation produces excess intracellular signaling. Such an increase in DRD2 signaling relative to DRD1 would contribute to the imbalances in dopaminergic neurotransmission characteristic of schizophrenia.

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Section: Discussionsupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Evidence That the BLOC-1 Protein Dysbindin Modulates Dopamine D₂Receptor Internalization and Signaling But Not D₁Internalization

Iizuka¹,

Sei²,

Weinberger³

et al. 2007

J. Neurosci.

120

109

View full text Add to dashboard Cite

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“…Neurochemical findings in cortex were then supported by changes in densities in dopamine-transporter immunoreactive fibers using a pixel based method; we obtained similar observations in initial studies using counts of labeled fibers by paired independent observers who were unaware of genotype. The greater fiber densities noted in knockouts and the elevated dopamine turnover (42) suggested by the altered ratios between dopamine and its major metabolites are each consistent with in vitro observations that CDH13-CDH13 interactions can inhibit outgrowth of CDH13-expressing neuronal processes (34). Microarray results that point to substantial changes in cortical expression of only the activitydependent transcription factor Npas4 (43) comport with both subtly altered cortical circuitry in the CDH13 knockouts and with the substantial specificity of the changes that CDH13 deletion induces.…”

Section: Discussionmentioning

confidence: 99%

Cadherin 13: Human cis-Regulation and Selectively Altered Addiction Phenotypes and Cerebral Cortical Dopamine in Knockout Mice

Drgonová

Walther

Hartstein

et al. 2016

Mol Med

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The cadherin 13 (CDH13) gene encodes a cell adhesion molecule likely to influence development and connections of brain circuits that modulate addiction, locomotion and cognition, including those that involve midbrain dopamine neurons. Human CDH13 mRNA expression differs by more than 80% in postmortem cerebral cortical samples from individuals with different CDH13 genotypes, supporting examination of mice with altered CDH13 expression as models for common human variation at this locus. Constitutive CDH13 knockout mice display evidence for changed cocaine reward: shifted dose response relationship in tests of cocaine-conditioned place preference using doses that do not alter cocaine-conditioned taste aversion. Reduced adult CDH13 expression in conditional knockouts also alters cocaine reward in ways that correlate with individual differences in cortical CDH13 mRNA levels. In control and comparison behavioral assessments, knockout mice display modestly quicker acquisition of rotarod and water maze tasks, with a trend toward faster acquisition of 5-choice serial reaction time tasks that otherwise displayed no genotype-related differences. They display significant differences in locomotion in some settings, with larger effects in males. In assessments of brain changes that might contribute to these behavioral differences, there are selective alterations of dopamine levels, dopamine/metabolite ratios, dopaminergic fiber densities and mRNA encoding the activity dependent transcription factor npas4 in cerebral cortex of knockout mice. These novel data and previously reported human associations of CDH13 variants with addiction, individual differences in responses to stimulant administration and attention deficit hyperactivity disorder (ADHD) phenotypes suggest that levels of CDH13 expression, through mechanisms likely to include effects on mesocortical dopamine, influence stimulant reward and may contribute modestly to cognitive and locomotor phenotypes relevant to ADHD.

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“…In immortalized lymphocytes, it might be difficult to observe the effect of dysbindin-1 and NRG-1 gene expression on their neuron-specific functions, for example, the effect of dysbindin-1 on glutamate and dopamine release, 5,6,29 and on the formation of synaptic vesicles 30 and the effect of NRG-1 on N-methyl D-aspartate receptor hypofunction. 31 However, we might be able to determine the effect of dysbindin-1 and NRG-1 genes expression on their functions which are common in multiple tissues using immortalized lymphocytes, for example, the effect of dysbindin-1 on phosphatidylinositol 3 kinase-Akt signaling 29 and the effect of NRG-1 on ErbB-Akt signaling.…”

Section: Discussionmentioning

confidence: 99%

“…[2][3][4] Furthermore, the Sandy mouse, which expresses no dysbindin-1, has been reported to have behavioral abnormalities, cognitive deficits and a synaptic dysfunction that is related to the pathophysiology of schizophrenia. [5][6][7] Identified risk variants of NRG-1 are associated with the reduced white matter volume that is observed in schizophrenic brains. 8 The NRG-1 gene spans 1.2 Mb 9 and gives rise to many structurally and functionally distinct isoforms, through alternative promoter usage.…”

Section: Introductionmentioning

confidence: 99%

Dysbindin-1 and NRG-1 gene expression in immortalized lymphocytes from patients with schizophrenia

et al. 2011

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The dysbindin-1 and neuregulin-1 (NRG-1) genes are related to schizophrenia. Expression studies in postmortem brains have revealed lower expression of dysbindin-1 and higher expression of NRG-1 in brain tissue from subjects with schizophrenia. In addition to the difficulty of sampling, the use of postmortem brain tissues is not ideal because these tissues are heterogeneous with respect to biochemical parameters, lifetime history of medications and physiological status at the time of death. In contrast, medication and environmental influences that could mask the genetic basis of differences in RNA expression are removed in immortalized lymphocytes by culturing. Only a few microarray analysis studies using immortalized lymphocytes in schizophrenia have been reported, and whether immortalized lymphocytes are an appropriate alternative to neuronal tissue remains controversial. In this study, we measured the mRNA expression levels of dysbindin-1, NRG-1 and two other genes (NPY1R and GNAO1) in immortalized lymphocytes from 45 patients with schizophrenia and 45 controls using real-time quantitative reverse transcriptase-PCR. No difference was observed between patients and controls with respect to the expression of dysbindin-1, NRG-1, NPY1R or GNAO1 gene. Our findings suggest that the gene expression profile of immortalized lymphocyte from schizophrenic patients is different from that in postmortem brain tissue at least with respect to the dysbindin-1 and NRG-1 genes. Journal of Human Genetics INTRODUCTIONSchizophrenia is a complex genetic disorder that is characterized by profound disturbances of cognition, emotion and social functioning. It affects B1% of the general population world wide. The dysbindin-1 and neuregulin-1 (NRG-1) genes are related to schizophrenia, 1 and the dysbindin-1 gene is also associated with cognitive functions. [2][3][4] Furthermore, the Sandy mouse, which expresses no dysbindin-1, has been reported to have behavioral abnormalities, cognitive deficits and a synaptic dysfunction that is related to the pathophysiology of schizophrenia. [5][6][7] Identified risk variants of NRG-1 are associated with the reduced white matter volume that is observed in schizophrenic brains. 8 The NRG-1 gene spans 1.2 Mb 9 and gives rise to many structurally and functionally distinct isoforms, through alternative promoter usage. These isoforms are divided into three classic groups: 10 type I (previously known as acetylcholine receptor inducing activity, heregulin or neu differentiation factor), type II (glia growth factor) and type III (cysteine-rich domain containing), which are based on distinct amino termini. Additional NRG-1 5¢ exons have

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High dopamine turnover in the brains of Sandy mice

Cited by 54 publications

References 29 publications

Evidence That the BLOC-1 Protein Dysbindin Modulates Dopamine D₂Receptor Internalization and Signaling But Not D₁Internalization

Evidence That the BLOC-1 Protein Dysbindin Modulates Dopamine D₂Receptor Internalization and Signaling But Not D₁Internalization

Cadherin 13: Human cis-Regulation and Selectively Altered Addiction Phenotypes and Cerebral Cortical Dopamine in Knockout Mice

Dysbindin-1 and NRG-1 gene expression in immortalized lymphocytes from patients with schizophrenia

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High dopamine turnover in the brains of Sandy mice

Cited by 54 publications

References 29 publications

Evidence That the BLOC-1 Protein Dysbindin Modulates Dopamine D2Receptor Internalization and Signaling But Not D1Internalization

Evidence That the BLOC-1 Protein Dysbindin Modulates Dopamine D2Receptor Internalization and Signaling But Not D1Internalization

Cadherin 13: Human cis-Regulation and Selectively Altered Addiction Phenotypes and Cerebral Cortical Dopamine in Knockout Mice

Dysbindin-1 and NRG-1 gene expression in immortalized lymphocytes from patients with schizophrenia

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Evidence That the BLOC-1 Protein Dysbindin Modulates Dopamine D₂Receptor Internalization and Signaling But Not D₁Internalization

Evidence That the BLOC-1 Protein Dysbindin Modulates Dopamine D₂Receptor Internalization and Signaling But Not D₁Internalization