Functional variants of the dopamine receptor D2 gene modulate prefronto-striatal phenotypes in schizophrenia

Bertolino, Alessandro; Fazio, Leonardo; Caforio, Grazia; Blasi, Giuseppe; Rampino, Antonio; Romano, Raffaella; Giorgio, Annabella Di; Taurisano, Paolo; Papp, Audrey C.; Pinsonneault, Julia K.; Wang, Daqing; Nardini, Marcello; Popolizio, Teresa; Sadée, Wolfgang

doi:10.1093/brain/awn248

Cited by 122 publications

(124 citation statements)

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“…Consistently, previous studies have found reduced AKT1 levels and phosphorilated GSK-3β (31) in patients with schizophrenia. Our results suggest that these earlier findings may be also because of the interaction between genetic variation in DRD2 and AKT1 genes, previously associated with schizophrenia phenotypes (23,39). Further studies addressing these effects at the neuronal level are needed to confirm these speculations.…”

Section: Discussionsupporting

confidence: 56%

“…In particular, the T allele shifts splicing from D2S to D2L, decreasing the D2S/D2L ratio relative to the G allele. This SNP has also been associated with behavior and brain activity during cognitive and emotion processing in healthy humans and in patients with schizophrenia (15,22,23). More specifically, the T allele has been associated with less efficient prefronto-striatal activity during working memory (23) and with putatively greater levels of striatal dopamine (24).…”

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confidence: 99%

“…This SNP has also been associated with behavior and brain activity during cognitive and emotion processing in healthy humans and in patients with schizophrenia (15,22,23). More specifically, the T allele has been associated with less efficient prefronto-striatal activity during working memory (23) and with putatively greater levels of striatal dopamine (24). DRD2 has also been weakly associated with diagnosis of schizophrenia (25).…”

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confidence: 99%

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DRD2/AKT1interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia

Blasi

Napolitano

Ursini

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The D2/AKT1/GSK-3β signaling pathway has been involved in the downstream intracellular effects of dopamine, in the pathophysiology of cognitive deficits and related brain activity in schizophrenia, as well as in response to treatment with antipsychotics. Polymorphisms in the D2 (DRD2 rs1076560) and AKT1 (AKT1 rs1130233) genes have been associated with their respective protein expression and with higher-order cognition and brain function, including attention. Given the strong potential for their relationship, we investigated the interaction of these polymorphisms on multiple molecular and in vivo phenotypes associated with this signaling pathway. We measured AKT1 and GSK-3β proteins and phosphorylation in human peripheral blood mononuclear cells, functional MRI cingulate response during attentional control, behavioral accuracy during sustained attention, and response to 8 wk of treatment with olanzapine in a total of 190 healthy subjects and 66 patients with schizophrenia. In healthy subjects, we found that the interaction between the T allele of DRD2 rs1076560 and the A allele of AKT1 rs1130233 was associated with reduced AKT1 protein levels and reduced phosphorylation of GSK-3β, as well as with altered cingulate response and reduced behavioral accuracy during attentional processing. On the other hand, interaction of these two alleles was associated with greater improvement of Positive and Negative Syndrome Scale scores in patients with schizophrenia after treatment with olanzapine. The present results indicate that these functional polymorphisms are epistatically associated with multiple phenotypes of relevance to schizophrenia. Our results also lend support to further investigation of this downstream molecular pathway in the etiology and treatment of this disorder.A large series of experimental data indicate that dopamine D2 receptors and schizophrenia are tightly related. First, these receptors are privileged targets of antipsychotic drugs, which antagonize their activity (1). Second, previous reports have suggested association between psychosis and relatively greater D2 density in striatum, even though change is moderate (2). Third, clinical symptoms and cognitive deficits have been associated with abnormal D2 signaling (3-12). The relationship between D2 receptors and cognitive deficits in schizophrenia is also supported by previous models postulating that relatively excessive D2 signaling may lead to lower cortical signal-to-noise ratio and reduced filtering of information, as well as blocking of distracting inputs (10-12). These brain processes contribute to different higherorder cognitive functions and are strongly involved in top-down modulation of attention (13,14). Consistent with these models, previous data have suggested that attentional behavior is affected by D2 genetic variation (15). Furthermore, deficits in attentional processing are centrally implicated in schizophrenia (16,17). In fact, patients with schizophrenia performing attentional tasks have abnormal activity in the cingulate cortex, a ...

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Section: Discussionsupporting

confidence: 56%

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confidence: 99%

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confidence: 99%

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DRD2/AKT1interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia

Blasi

Napolitano

Ursini

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Recent studies on DISC1, BABRB2, DRD2 and AKT1, top-ranked SZ susceptibility genes based on meta-analysis of multiple case-control association studies all support this allele-expression regulatory mechanism. [29][30][31][32][33] However, the search for connection between risk genetic polymorphisms and brain GRIN2B mRNA levels, another top-ranked risk gene in SZ, resulted in negative findings. As such, the study focused on the overall mRNA level, not on variants.…”

Section: Discussionmentioning

confidence: 99%

An integrated genomic analysis of gene-function correlation on schizophrenia susceptibility genes

Chu

Liu

2010

J Hum Genet

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Schizophrenia is a highly complex inheritable disease characterized by numerous genetic susceptibility elements, each contributing a modest increase in risk for the disease. Although numerous linkage or association studies have identified a large set of schizophrenia-associated loci, many are controversial. In addition, only a small portion of these loci overlaps with the large cumulative pool of genes that have shown changes of expression in schizophrenia. Here, we applied a genomic gene-function approach to identify susceptibility loci that show direct effect on gene expression, leading to functional abnormalities in schizophrenia. We carried out an integrated analysis by cross-examination of the literature-based susceptibility loci with the schizophrenia-associated expression gene list obtained from our previous microarray study (Journal of Human Genetics (2009) 54: 665-75) using bioinformatic tools, followed by confirmation of gene expression changes using qPCR. We found nine genes (CHGB, SLC18A2, SLC25A27, ESD, C4A/C4B, TCP1, CHL1 and CTNNA2) demonstrate gene-function correlation involving: synapse and neurotransmission; energy metabolism and defense mechanisms; and molecular chaperone and cytoskeleton. Our findings further support the roles of these genes in genetic influence and functional consequences on the development of schizophrenia. It is interesting to note that four of the nine genes are located on chromosome 6, suggesting a special chromosomal vulnerability in schizophrenia.

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“…In previous reports, we have found that the T allele of a single-nucleotide polymorphism (SNP) positioned in intron 6 (rs1076560, G4T) and affecting DRD2 splicing is associated with a lower ratio of expression of D2S/D2L compared with the G allele. Furthermore, the T allele is associated with altered working memory prefrontal physiology and behavior (Bertolino et al, 2009b;Zhang et al, 2007). This effect may reflect lower stability of prefrontal response networks during working memory processing (Seamans and Yang, 2004), which is driven by greater D2 postsynaptic signaling putatively associated with the T allele (Usiello et al, 2000;Zhang et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Variation in Dopamine D2 and Serotonin 5-HT2A Receptor Genes is Associated with Working Memory Processing and Response to Treatment with Antipsychotics

Blasi

Selvaggi

Fazio

et al. 2015

Neuropsychopharmacol

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Dopamine D2 and serotonin 5-HT2A receptors contribute to modulate prefrontal cortical physiology and response to treatment with antipsychotics in schizophrenia. Similarly, functional variation in the genes encoding these receptors is also associated with these phenotypes. In particular, the DRD2 rs1076560 T allele predicts a lower ratio of expression of D2 short/long isoforms, suboptimal working memory processing, and better response to antipsychotic treatment compared with the G allele. Furthermore, the HTR2A T allele is associated with lower 5-HT2A expression, impaired working memory processing, and poorer response to antipsychotics compared with the C allele. Here, we investigated in healthy subjects whether these functional polymorphisms have a combined effect on prefrontal cortical physiology and related cognitive behavior linked to schizophrenia as well as on response to treatment with secondgeneration antipsychotics in patients with schizophrenia. In a total sample of 620 healthy subjects, we found that subjects with the rs1076560 T and rs6314 T alleles have greater fMRI prefrontal activity during working memory. Similar results were obtained within the attentional domain. Also, the concomitant presence of the rs1076560 T/rs6314 T alleles also predicted lower behavioral accuracy during working memory. Moreover, we found that rs1076560 T carrier/rs6314 CC individuals had better responses to antipsychotic treatment in two independent samples of patients with schizophrenia (n ¼ 63 and n ¼ 54, respectively), consistent with the previously reported separate effects of these genotypes. These results indicate that DRD2 and HTR2A genetic variants together modulate physiological prefrontal efficiency during working memory and also modulate the response to antipsychotics. Therefore, these results suggest that further exploration is needed to better understand the clinical consequences of these genotype-phenotype relationships.

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Functional variants of the dopamine receptor D2 gene modulate prefronto-striatal phenotypes in schizophrenia

Cited by 122 publications

References 57 publications

DRD2/AKT1interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia

DRD2/AKT1interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia

An integrated genomic analysis of gene-function correlation on schizophrenia susceptibility genes

Variation in Dopamine D2 and Serotonin 5-HT2A Receptor Genes is Associated with Working Memory Processing and Response to Treatment with Antipsychotics

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