Roles of the Akt/GSK-3 and Wnt Signaling Pathways in Schizophrenia and Antipsychotic Drug Action

Freyberg, Zachary; Ferrando, Stephen J.; Javitch, Jonathan A.

doi:10.1176/appi.ajp.2009.08121873

Cited by 250 publications

(219 citation statements)

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“…Downstream of D2 receptors, different molecular pathways have been identified: the classic cAMP-PKA pathway and another cAMP-independent pathway that includes the serine/threonine protein kinase AKT1, which phosphorylates to inhibit another protein kinase, GSK-3β (reviewed in ref. 26). The specific relationship between D2 receptor signaling and AKT1 has been elucidated by data indicating that D2 stimulation by dopamine inhibits AKT1 signaling through dephosphorylation via the β-arrestin 2/phosphatase PP2A complex (27,28) (for review, see refs.…”

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confidence: 99%

“…Importantly, AKT1 levels in lymphoblasts and in prefrontal cortex of patients with schizophrenia are reduced (31,32). Furthermore, clozapine, a D2 antagonist antipsychotic, increases AKT1 and GSK-3β phosphorylation, as well as total cellular and intranuclear levels of β-catenin (33), a crucial factor for gene expression that is inhibited by GSK-3β activity (26).…”

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confidence: 99%

“…In particular, given the known reciprocal relationship between D2 and AKT1 and their effects on GSK-3β activity (26), as the more proximal phenotype, we evaluated the interaction between DRD2 and AKT1 SNPs on AKT1 and GSK-3β protein levels and phosphorylation in human blood cells. Because this experiment suggested functional epistatic downstream effects of these two polymorphisms, we performed further specific analyses.…”

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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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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 Wnt family of signaling molecules participates in a broad range of processes, from neurogenesis to synaptic plasticity. Several Wnt pathway components have been implicated in the pathogenesis of schizophrenia and Alzheimer's, raising the question of how this pathway functions at the synapse [33,34]. At the Drosophila NMJ, the Wnt pathway signals bidirectionally to mediate synaptic growth in response to patterned neuronal stimulation [35].…”

Section: Activity-dependent Synaptic Development Depends On Intercellmentioning

confidence: 99%

“…Single nucleotide polymorphisms in GSK-3β are associated with schizophrenia, and GSK-3β was recently found to interact with DISC1, a major schizophrenia susceptibility gene [33,36]. Postsynaptically, Wnt signaling causes translocation of the cleaved receptor Frizzled into the nucleus, which promotes growth of the postsynaptic membrane [35,37].…”

Section: Activity-dependent Synaptic Development Depends On Intercellmentioning

confidence: 99%

Synapse development in health and disease

Melom

Littleton

2011

Current Opinion in Genetics & Development

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SummaryRecent insights into the genetic basis of neurological disease have led to the hypothesis that molecular pathways involved in synaptic growth, development, and stability are perturbed in a variety of mental disorders. Formation of a functional synapse is a complex process requiring stabilization of initial synaptic contacts by adhesive protein interactions, organization of pre-and post-synaptic specializations by scaffolding proteins, regulation of growth by intercellular signaling pathways, reorganization of the actin cytoskeleton, and proper endosomal trafficking of synaptic growth signaling complexes. Many neuropsychiatric disorders, including autism, schizophrenia, and intellectual disability, have been linked to inherited mutations which perturb these processes. Our understanding of the basic biology of synaptogenesis is therefore critical to unraveling the pathogenesis of neuropsychiatric disorders.

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