Opinion
Schizophrenia as a GSK-3 dysregulation disorder

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Converging evidence suggests that the regulation of glycogen synthase kinase 3 (GSK-3) might be important in schizophrenia. Atypical and typical antipsychotic drugs alter GSK-3 activity, as do drugs that induce psychosis. GSK-3 regulatory pathways are altered in schizophrenia, and many of the genes associated with schizophrenia directly or indirectly regulate GSK-3 activity. We propose a variant on the neurodevelopment and dopamine hypotheses of schizophrenia, whereby (i) an early dysfunction in GSK-3 regulation has neurodevelopmental consequences that predispose to disease and (ii) dysfunction in GSK-3 regulation in the adult brain alters dopamine signalling events, causing psychotic symptoms and cognitive dysfunction. If, as we suggest, GSK-3 regulation is crucial to schizophrenia, the Wnt and insulin signalling pathways become targets for therapy.

Introduction

Understanding the molecular pathogenesis of schizophrenia has proved elusive, although there is no shortage of interesting hypotheses. One consistent finding is the evidence that dopamine signalling, in particular through the D2 receptor, is central to schizophrenia [1]. Dopamine supersensitivity, and an increase in high-affinity D2 receptors, is a common feature of drugs that induce psychosis. Add the observation that antipsychotic drugs exert their actions through the high-affinity state D2 receptor, and the dopamine hypothesis of schizophrenia is a powerful one. However, if D2 supersensitivity is a feature of schizophrenia, what are the consequences for neurones and might there be other factors that influence psychosis pathogenesis downstream of the receptor? Recent findings have linked the intracellular pathways that function downstream of the dopamine D2 receptor to glycogen synthase kinase 3 (GSK-3) [2], a kinase already implicated in schizophrenia. Thus, in addition to signalling through the second messengers cAMP and Ca2+, activation of the D2 receptor stimulates the assembly of a complex containing β-arrestin 2, protein phosphatase 2A (PP2A), the GSK-3 regulator AKT and, probably, also GSK-3 itself 2, 3. PP2A is a negative regulator of AKT, and AKT negatively regulates GSK-3, suggesting a complex that fine-tunes the response of the cell to dopamine through D2 receptors. As Bibb [2] notes, ‘there is more to blocking D2 receptor activity than reducing the intracellular cAMP concentration, and the signalling pathways that make [D2 antagonists such as haloperidol and risperidone] effective remain to be fully elucidated’. Indeed, the increase in data implicating the multiple pathways that regulate the activity of GSK-3 in the pathophysiology of this disease opens up the potential of an entirely new library of therapeutic targets.

Here, we make the case, firstly, that it is notable that many of the genes associated with schizophrenia function directly or indirectly on GSK-3 regulatory pathways, and, secondly, that these pathways are altered in schizophrenia, as evidenced by post mortem studies, studies on peripheral cells and, most strikingly, by the association of schizophrenia with diabetes. We then consider the overwhelming evidence that drugs that induce psychosis, and those used to treat psychosis, alter GSK-3 signalling. Finally, we speculate that disruption of the GSK-3 regulatory pathways could have a role both in the neurodevelopmental origins of schizophrenia and also in some of the symptoms – especially the cognitive deficits.

Section snippets

GSK-3 and its regulation through Wnt and insulin signalling

There are actually two highly homologous GSK-3 enzymes, GSK-3α and GSK-3β, derived from separate genes. As their names indicate, they were first discovered through their roles in the insulin signalling pathway, in which they control glycogen synthesis by regulating the activity of glycogen synthase. Insulin signals through the tyrosine kinase activity of its receptor to activate protein kinase B (PKB, also known as AKT) through the phosphatidylinositol 3-kinase (PI 3-kinase) pathway. PKB, in

Genes associated with schizophrenia also function in GSK-3 signalling

After many years of small and nonreplicating studies, schizophrenia geneticists are scenting success in their hunt for susceptibility genes. Owen et al. [6] listed six genes for which they consider the evidence for association with schizophrenia to be reasonably strong; Straub and Weinberger [7] listed a further 11 with variable levels of evidence; and Ross et al. [8] have added two more, giving a total of 19 potential risk genes. To these, we might add NOTCH4, for which meta-analysis suggests

Wnt signal alteration in schizophrenia

There is also evidence from expression studies linking GSK-3 regulation to schizophrenia. The first suggestion that GSK-3 might be a player in the pathogenesis of schizophrenia came with a report that lymphocytes from patients showed a deficit in the activity of a phosphatase that was restored by exogenous application of the activating kinase – GSK-3α [25]. GSK-3α protein and activity was shown to be decreased in a small number of cases relative to controls in this study. Two subsequent studies

Evidence that GSK-3 signalling is altered by psychoactive compounds

If GSK-3 regulation is altered in schizophrenia, it might be predicted that psychoactive compounds would alter GSK-3 signalling. The evidence is growing that this is the case. Both typical and atypical antipsychotic drugs have been studied in relation to GSK-3; the phosphorylation, and hence inhibition, of GSK-3 activity is stimulated by clozapine in human neuroblastoma cells [34] and by haloperidol in mice in vivo [26]. Interestingly, in the former experiment, an inhibitor of PI 3-kinase

The effects of GSK-3 regulation on behaviour in vivo

Complete mouse models of schizophrenia are lacking but two behaviours commonly used as possible correlates of schizophrenia are social behaviours and sensorimotor gating [43]. The latter refers to the inability to pay selective attention to the environment and filter or ‘gate’ out unwanted stimuli. This characteristic, lacking in people with schizophrenia, can be measured in both man and mouse by prepulse inhibition (PPI), in which a prepulse reduces a startle response. PPI is decreased in

Schizophrenia, diabetes and Alzheimer's disease

As discussed earlier, GSK-3 is regulated principally through Wnt and through insulin signalling. A failure in insulin signalling underlies maturity-onset or type 2 diabetes mellitus, a disorder that is at least 2–4 times more prevalent in people with schizophrenia than in the general population [47]. As others have noted, diabetes and schizophrenia have been associated with each other for over 100 years [48]. Henry Maudsley knew that the two conditions occurred frequently together;

GSK-3 regulation and the pathophysiology of schizophrenia

How might a disruption in the regulation of GSK-3 influence the development of schizophrenia? We suggest that such a disruption might result in neurodevelopmental changes and then, in adults with the condition, in the cognitive symptoms that are part of the symptom complex.

Schizophrenia is almost certainly a neurodevelopmental disorder [58], and GSK-3 regulatory pathways have long been of interest to neurodevelopmental biologists, mostly because of Wnt signalling [59], but insulin pathway

Conclusions and some suggestions

The evidence linking GSK-3 regulation and schizophrenia comes from a surprisingly wide range of experimental models and human observations. This is the first time that a body of work has described, at a molecular level, a possible insight into schizophrenia that goes beyond the receptor. In summary, the evidence thus far is that:

  • GSK-3 protein levels and/or activity are altered in the brain and lymphocytes from schizophrenic individuals.

  • A high proportion of the genes that have been associated

Acknowledgements

Work in our laboratories on GSK-3 and its regulation is supported by the Wellcome Trust.

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