Schizophrenia Research Forum - A Catalyst for Creative Thinking

Lithium Takes Indirect Route to Inhibit GSK-3β

Adapted from a story that originally appeared on the Alzheimer Research Forum.

20 January 2008. Lithium is an old and valued drug for mood disorders, whose mechanism of action remains murky. Inhibition of the glycogen synthase kinase 3 β (GSK-3β) has been implicated, but lithium inhibits this enzyme only weakly and requires much higher concentrations to block it in vitro than to elicit a therapeutic effect in vivo. Now, work from the lab of Marc Caron at Duke University Medical Center, Durham, North Carolina, published in the January 11 issue of Cell, shows that lithium can inhibit GSK-3 in vivo, but does so indirectly. It disrupts its signaling through the upstream kinase Akt. Specifically, lithium breaks up a magnesium-dependent association of Akt with the scaffolding protein β-arrestin 2 (β-ARR2). That results in activation of Akt, which then phosphorylates and inhibits GSK-3β.

There are some provisional links between members of this pathway and schizophrenia, including genetic association studies implicate AKT1 as a susceptibility gene (see SchizophreniaGene entry), and studies that suggest that antipsychotic drugs regulate Akt/GSK-3β signaling (e.g., Roh et al., 2007; Li et al., 2007; SRF related news story).

First author Jean-Martin Beaulieu used β-arrestin 2 (βARR2) knockout mice to probe the role of this scaffolding protein in lithium action. βARR2 organizes a signaling complex on G protein-coupled receptors that includes the Akt kinase. The complex does not require G proteins for activity, and thus represents an alternative signaling pathway utilized by GPCRs. Beaulieu and colleagues show that lithium injection into the striatum of mice led to activation of Akt and the subsequent inactivation of GSK-3β kinase. Lithium had no such effect in βARR2 knockout mice, nor did the mice show the expected behavioral effects of lithium treatment. The knockout mice were also refractory to chronic changes in the activity of Akt or GSK-3, and associated expression of the β-catenin gene, upon prolonged lithium treatment.

In-vitro immunoprecipitation studies showed that βARR2 was required to see interaction of Akt with protein phosphatase 2A in a signaling complex. Lithium prevented the association of Akt with βARR2 or Akt and two different subunits of PP2A. A similar effect was seen in vivo. Lithium broke up the complex by competing with magnesium, which was required for the interaction. Importantly, all these effects occurred at concentrations of lithium that are attained therapeutically. The effects of lithium appeared specific to the GPCR-mediated regulation of the Akt pathway, and the drug did not interfere with other functions of either βARR2 or G protein-dependent receptor signaling. The results indicate that lithium may not generally inhibit the pathway, but instead offers a means of precisely targeting selective GPCR functions that rely on arrestin-containing signaling complexes.

These pathways are not currently front and center in schizophrenia research, but several groups, in particular the laboratories of Joseph Gogos and Maria Karayiorgou at Columbia University, New York, have investigated the role of AKT in both schizophrenia etiology and antipsychotic drug effects (see SRF related news story). And, as Beaulieu and colleagues point out, lithium is used to enhance the effects of antipsychotic drugs in refractory cases. "Identification of the Akt:bArr2:PP2A signaling complex as a molecular target of lithium thus provides a mechanism by which this pharmacological agent may enhance the actions of other drugs acting through Akt/GSK3 signaling by preventing the inhibition of Akt by PP2A," they write.—Pat McCaffrey.

Reference:
Beaulieu J, Marion S, Rodriguiz RM, Medvedev IO, Sotnikova TD, Ghisi V, Wetsel WC, Lefkowitz RJ, Gainetdinov RR, Caron MG. A b-arrestin 2 Signaling Complex Mediates Lithium Action on Behavior. Cell. 2008 Jan 11;132:125-136. Abstract

Comments on Related News


Related News: Playing on Without AKT1: Subtle Cortical Deficits Suggest Vulnerabilities

Comment by:  Takeo YoshikawaAkihiko Takashima
Submitted 30 November 2006
Posted 30 November 2006
  I recommend the Primary Papers

In this study, Karayiorgou and Gogos’s group have conducted a meticulous anatomical analysis of pyramidal cell dendritic structures in the prefrontal layer V cortex, as well as genome-wide expression and pharmaco-behavioral analyses, focusing on prefrontal functions in Akt1-deficient mice. The study examines the reduced (or altered) AKT1-GSK3β signalling theory of schizophrenia, proposed by this (Emamian et al., 2004) and other groups.

AKT1 as a genetic susceptibility gene for schizophrenia shows promise in the Caucasian population but this is not reflected in Asian populations as evidenced by our results (Ide et al., 2006). In addition, even in Caucasians, true causal variants have not been identified. Because of this, schizophrenia researchers are interested in observing disease-relevant phenotypes in Akt1-deficient mice. In this study, they have detected morphological and functional alterations of frontal cortex-related traits in mutant mice using state-of-the-art techniques.

To further strengthen AKT1 as a candidate disease gene in schizophrenia, several issues need to be addressed in the near future. For instance, if a reduction of AKT1 signalling occurs in the brain, tau should be hyper-phosphorylated by activated GSK3β, which in turn will lead to the formation of neurofibrillary tangles (NFTs) as seen in Alzheimer’s disease. Therefore, it would be interesting to determine whether Akt1-deficient mice show a similar pattern of tau phosphorylation. Accumulating evidence suggests that hyper-phosphorylated tau may affect a variety of neuronal functions. Our recent biochemical analyses failed to reveal any significant reduction of AKT-mediated signalling in the prefrontal cortex of schizophrenic brains or the expected inverse correlation between phosphorylation levels of AKT and tau (Ide et al., 2006). This highlights the difficulty of examining protein phosphorylation status using postmortem brains, where results are often confounded by multiple, uncontrollable factors.

Another important but poorly understood point is the functional relationship among subspecies of the AKT family (at least AKT1, AKT2 and AKT3) and GSK3 (GSK3α and GSK3β) (for example see Sale et al., 2005). We look forward to continuing multidisciplinary studies aimed at unravelling the role of the AKT cascade, including the clarification of downstream pathways (Datta et al., 1999; (O’Mahony et al., 2006) in schizophrenia pathology.

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Related News: Hidden Complexity Seen in Serotonin Signaling

Comment by:  Patricia Estani
Submitted 23 February 2008
Posted 26 February 2008
  I recommend the Primary Papers

Related News: Hidden Complexity Seen in Serotonin Signaling

Comment by:  Atheir Abbas
Submitted 25 February 2008
Posted 27 February 2008
  I recommend the Primary Papers

Implicit in the findings of Schmid et al. is the idea that the relationship among ligand, receptor signaling, and cellular context is an extremely complex one that will take a great deal more work to tease out. Thus, Dr. Bryan Roth has proposed on a number of occasions (see, for example, Gray and Roth, 2007; Abbas and Roth, 2005) that novel approaches for drug discovery may prove more effective in producing schizophrenia drugs that have greater therapeutic efficacy with lower side effect liability. Since it will likely be many years before the field has a detailed understanding of the "nitty-gritty" of the receptor signaling and trafficking relevant to schizophrenia and its treatment, we have suggested a number of approaches that are less reliant on such information.

For example, approaches based on screening for drugs that either mimic the gene expression profiles of gold standard drugs such as clozapine or normalize schizophrenia-associated changes in gene expression are being explored. Another approach is behavior-based screening, in which targeted screens are performed with drugs to find those that have efficacy in animal disease models. A further related approach, exemplified by Psychogenics' Smartcube(TM) (the associated database is called Smartbase[TM]) involves injecting drugs and monitoring the resulting behavior using computer-based machine learning to generate a multidimensional behavioral signature for gold standard drugs. Drugs can then be screened to look for those that mimic gold standard drugs in terms of their signatures. Though Psychogenics does not appear to have done much (at least publicly) with this approach, it represents the sort of innovative thinking that may prove fruitful in future behavior-based drug discovery efforts since it is not dependent on knowing anything about the mechanism. In the end, at least in the near future, we believe such approaches may prove extremely useful in drug discovery efforts since they do not rely on extensive mechanistic knowledge of the processes underlying schizophrenia.

References:

Gray JA, Roth BL. The pipeline and future of drug development in schizophrenia. Mol Psychiatry. 2007 Oct ;12(10):904-22. Abstract

Abbas A, Roth B. Progress towards better understanding and treatment of major psychiatric illnesses. Drug Discov Today. 2005 Jul 15;10(14):960-2. Abstract

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Related News: An Arrestin Development: Antipsychotic Drugs Hit Dopamine Signaling in New Way

Comment by:  Zachary Z. FreybergEneko UrizarHolly MooreJeffrey Lieberman (SRF Advisor)Jonathan Javitch
Submitted 30 December 2008
Posted 30 December 2008

Reevaluation of the dopamine D2 receptor in the treatment of schizophrenia: Novel intracellular mechanisms as predictors of antipsychotic efficacy
Since the advent of antipsychotic medications, there have been many speculations about their precise mechanisms of therapeutic action. Although it is apparent that blockade of dopamine D2 receptors (D2R) is crucial to the efficacy of all current antipsychotic medications, it is not clear which signaling events downstream of the D2R must be blocked for the therapeutic actions of antipsychotics and which events, when blocked, lead instead to side effects.

The best characterized D2R-mediated signaling pathways involve coupling of the receptor to pertussis toxin-sensitive G proteins of the Gi and Go subfamilies (Sidhu and Niznik, 2000), through which D2R activation results in a decrease in cyclic AMP (cAMP). D2R activation can also have a number of other effects, including enhancement of specific potassium currents, inhibition of L-type calcium currents, mediation of extracellular signal-regulated kinase 1 (ERK1) and potentiation of arachidonic acid release (Beom et al., 2004; Missale et al., 1998; Perez et al., 2006; Hernández-López et al., 2000). There is growing evidence that D2Rs can interact with a number of membrane-bound or intracellular proteins, which may further modulate signaling specificity (reviewed in Terrillon and Bouvier, 2004; Ferré et al., 2007a). In particular, D2R heteromerization may result in a switch from Gi/o coupling to Gs (i.e., through D2R and cannabinoid 1 receptor interaction) (Kearn et al., 2005) or to coupling with Gq (as suggested in D2R and D1R interactions) (Rashid et al., 2007). Moreover, heteromerization between D2R and other receptors such as the adenosine A2A receptor may allow for reciprocal modulation of D2R function (Ferré et al., 2007a; Ferré et al., 2007b). It also has been suggested that calcium signaling mechanisms may modulate D2R’s signaling efficacy; interaction between D2R and calcium-binding protein S100B results in enhanced D2R intracellular signaling (Liu et al., 2008; Stanwood, 2008).

The interaction between D2R and arrestin has received increasing attention. Following D2R activation, D2R signaling is attenuated by recruitment of arrestin 3 to the cell surface where it binds to the receptor (Klewe et al., 2008; Lan et al., 2008a ; Lan et al., 2008b), leading to inactivation and internalization of the D2R. Arrestin 3 also binds Akt—a serine/threonine kinase involved in multiple cellular functions and implicated clinically in schizophrenia (Arguello and Gogos; 2008; Beaulieu et al., 2005; Brazil and Hemmings, 2001; Brazil et al., 2004; Emamian et al., 2004; Kalkman, 2006). Following D2R activation by dopamine, the signaling scaffold formed by arrestin 3, while facilitating receptor desensitization and internalization, also recruits Akt into a complex with the phosphatase PP2A, which dephosphorylates and consequently inactivates Akt (Beaulieu et al., 2007a ). Thus, D2R activation inhibits Akt activity through an arrestin-dependent but G protein-independent pathway (Beaulieu et al., 2007a ; Beaulieu et al., 2007b). Curiously, the mood stabilizer, lithium, has been shown to disrupt the arrestin 3-Akt-PP2A complex, thereby preventing dopamine-induced dephosphorylation of Akt and blocking amphetamine-induced locomotion (Beaulieu et al., 2008). Moreover, amphetamine-induced locomotion is greatly diminished in arrestin 3 knockout mice, suggesting that this pathway is critical to at least some psychostimulant effects (Beaulieu et al., 2005).

Using newly developed BRET (bioluminescent resonance energy transfer) biosensors in assays that measure direct protein-protein interactions within the living cell, recent studies have demonstrated that antipsychotic medications prevent arrestin 3 recruitment by blocking D2R activation (Klewe et al., 2008; Masri et al., 2008). Masri et al. (2008) hypothesized that antipsychotic drugs achieve their therapeutic effect through a common mechanism involving blockade of arrestin-mediated signaling (Masri et al., 2008). Masri et al. (2008) also demonstrated that nearly all antipsychotics tested (including haloperidol, clozapine, olanzapine, desmethylclozapine, chlorpromazine, quetiapine, risperidone and ziprasidone) behave as inverse agonists to decrease constitutive G protein signaling as well as to prevent the agonist quinpirole from inhibiting cAMP synthesis (via D2R-mediated Gi/o signaling). The lone exception, aripiprazole, behaved as a partial agonist instead of as an inverse agonist of the G protein mediated effects. The latter finding is consistent with previous studies highlighting aripiprazole’s ability to differentially modulate various G protein-mediated effector pathways, a property termed “functional selectivity” (Mailman, 2007; Urban et al., 2007). Using the BRET assay, Klewe et al. (2008) and more recently Masri et al. (2008) demonstrated that all antipsychotics, including aripiprazole, block arrestin 3 recruitment. This finding has led Masri et al. (2008) to suggest that blockade of arrestin 3 recruitment to the D2R, and not modulation of G-protein-mediated pathways, is a common and specific property of all current antipsychotics and may be used to predict the antipsychotic efficacy of drugs in development (Masri et al., 2008). This hypothesis remains to be tested and at present appears to lean heavily on the evidence for aripiprazole’s atypical effects on constitutive (non-agonist-dependent) D2R-mediated G-protein signaling. Indeed, the fact that lithium acts to prevent arrestin-mediated signaling in response to amphetamine but is not an effective antipsychotic in monotherapy suggests that antipsychotic action may be more complex than simple blockade of D2R-mediated arrestin signaling. In addition, the ability of antipsychotics, including aripiprazole, to block agonist binding to the D2R and thus activation of the receptor, makes it likely that agonist-induced activity in multiple signaling pathways will also be blocked by these drugs.

Despite the paucity of direct evidence for D2R-arrestin coupling as the mechanism underlying the antipsychotic effects of drugs, the hypothesis remains quite intriguing Given that Akt and its downstream target GSK-3 (glycogen synthase kinase-3) have been implicated in schizophrenia in a number of genetic and postmortem studies, and the Akt/GSK-3 pathway might represent an opening into alternative therapeutics of schizophrenia. Akt is a serine/threonine kinase that may have significant roles in synaptic physiology and neurodegeneration (Brazil et al., 2004). Recruited to the cell surface by binding to phosphatidylinositol 3,4,5 trisphosphate, Akt is activated via phosphorylation of 3-phosphoinoitide-dependent protein kinase 1 (PDK1) and the rictor-mTOR complex (Brazil and Hemmings, 2001; Sarbassov et al., 2005). Once active, Akt phosphorylates GSK-3, thereby inactivating it. Since D2R activation leads to inactivation of Akt, this also results in increased GSK-3 activity (Beaulieu et al., 2004; Lovestone et al., 2007). GSK-3 activity also plays an important role in modulating the dopaminergic response to amphetamine. Amphetamine’s stimulation of DAT-mediated dopamine efflux and subsequent D2R stimulation likely results in Akt inactivation and increased GSK-3 activity. Rats treated with the specific GSK-3 inhibitor, AR-A014418, failed to display amphetamine-induced hyperactivity (Gould et al., 2004). Similarly, heterozygous GSK-3β knockout mice (expressing approximately half of wildtype levels of GSK-3β) displayed significantly reduced levels of locomotor activity following amphetamine treatment (Beaulieu et al., 2004). Additionally, treatment of dopamine transporter (DAT) knockout mice with multiple GSK-3 inhibitory drugs inhibited the ordinarily hyperactive behavior of the non-treated DAT knockout mice (Beaulieu et al., 2004).

In a mouse model, acute and chronic haloperidol treatment was shown to increase levels of active, phosphorylated Akt isoform Akt1 and increased phosphorylation and inactivation of GSK-3β (Emamian et al., 2004). Thus, it was suggested that haloperidol treatment may compensate for the decreased levels of endogenous Akt1 in the frontal cortex of people with schizophrenia (Emamian et al., 2004). Atypical antipsychotics also impact on the regulation of Akt and GSK-3β activities. For example, treatment with clozapine results in increased levels of phosphorylated GSK-3β (Kang et al., 2004; Sutton et al., 2007). Interestingly, however, differences between haloperidol and atypical antipsychotics have emerged in the kinetics of Akt/GSK-3 phosphorylation, the levels of proteins expressed following drug exposure, and the signaling pathways that are preferentially activated (Roh et al., 2007).

The abilities of antipsychotic drugs to activate distinct signaling pathways to mediate their ostensible differential pharmacologic effects would suggest clinical variation in their therapeutic effects. However, meaningful differences in the clinical effects of these compounds have not been clearly or consistently evident. The initial reports of superior efficacy of the so-called second generation or atypical antipsychotics on measures of psychosis (Kane et al., 1988), negative symptoms (Tollefson et al., 1997), cognitive deficits (Keefe et al., 1999), relapse prevention (Csernansky et al., 2002), adherence (Wahlbeck et al., 2001) and illness progression (Lieberman et al., 2005a), have not been borne out by more recent studies (Geddes et al., 2000; Lieberman et al., 2005b; Jones et al., 2006; Leucht et al., 2008). Indeed, the differences between antipsychotic drugs are most evident in the types, frequency and severity of side effects rather than in their therapeutic actions (Leucht et al., 1999; Allison et al., 1999; Henderson et al., 2005). In this regard the emerging pattern of variation in the molecular mechanisms of antipsychotic drugs in the face of their common clinical profiles resembles what was previously observed with the variability in neuroreceptor binding profiles (Kinon and Lieberman, 1996). The marked differences in the affinities and selectivity of the various antipsychotics for the receptors of different neurotransmitters were thought to underlie a rich pattern of clinical variation in the therapeutic actions of this group of drugs (Miyamoto et al., 2005). However, this hypothesis has not been supported by clinical studies (Lieberman, 2006; Lewis and Lieberman, 2008).

Nevertheless, there is reason to be hopeful that through functional selectivity, or other potential actions, the abilities of drugs to engage different signaling pathways will confer novel therapeutic effects that will improve the efficacy of treatments. In this context, the studies of Masri et al. (2008) and Klewe et al. (2008) highlight the plausibility that D2R/arrestin 3 modulation of Akt and GSK-3 activity is an important mechanism underlying psychosis and a potential target for future antipsychotic drugs. Further study of this pathway, including studies designed to reverse the effects of D2R antagonists or partial agonists (antipsychotic drugs) with systematic differential manipulation of the signaling pathways induced by D2R activation, is likely to be a fruitful path toward the development of novel treatments for schizophrenia-related disorders.

Acknowledgements: The authors would like to acknowledge the generous support of the Lieber Center for Schizophrenia Research at Columbia University

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Related News: DISC1: A Matter of Life or Death for Neural Progenitors

Comment by:  Khaled Rahman
Submitted 26 March 2009
Posted 26 March 2009

Mao and colleagues present an impressive body of work implicating GSK3β/β-catenin signaling in the function of Disc1. However, several key experimental controls are missing that detract from the impact of their study, and it is unclear whether this function of Disc1 among its many others is the critical link between the t(1;11) translocation and psychopathology in the Scottish family.

The results of Mao et al. suggest that acute knockdown of Disc1 in embryonic brain causes premature exit from the proliferative cell cycle and premature differentiation into neurons. In fact, they observe fewer GFP+ cells in the VZ/SVZ and greater GFP+ cells within the cortical plate. This is in contrast to the study by Kamiya et al. (2005), in which they find that knocking down Disc1 caused greater retention of cells in the VZ/SVZ and fewer in the cortical plate, suggesting retarded migration. Although the timing of electroporation (E13 vs. E14.5) and examination (E15 vs. P2) differed between the two studies, these results are not easily reconciled.

The authors also suggest that they can rescue the deficits in proliferation by overexpressing human wild-type DISC1, stabilizing β-catenin expression, or inhibiting GSK3β activity, and thus conclude that Disc1 is acting through this pathway. This conclusion, however, rests on an error in logic. If increasing X causes an increase in Y, and decreasing Z causes a decrease in Y, this does not mean that X and Z are operating via the same mechanism. In fact, overexpressing WT-DISC1, stabilizing β-catenin, or inhibiting GSK3β activity all increase proliferation in control cells. Thus, the fact that these manipulations also work in progenitors with Disc1 silenced only tells us that these effects are independent or downstream of Disc1. What are needed are studies that show a differential sensitivity of Disc1-silenced cells to manipulations of β-catenin or GSK3β. In other words, is there a shift in the dose response curves? This is what is to be expected given that Mao et al. show changes in β-catenin levels and changes in the phosphorylation of GSK3β substrates in Disc1 silenced cells.

Furthermore, it is surprising that a restricted silencing of Disc1 in the adult dentate gyrus produces changes in affective behaviors, when total ablation of dentate neurogenesis in the adult produces little effects on depression-related behaviors (Santarelli et al., 2003; Airen et al., 2007). The fact that inhibiting GSK3β increases proliferation in both control and Disc1 knockdown animals to a similar degree suggests that the “rescue” of any behavioral deficits is independent of the drug’s effects on proliferation. Correlating measures of proliferation with behavioral performance would help address this issue.

How this study will lead to new or improved therapeutic interventions is also an open question. Lithium is well known for its mood-stabilizing properties, and this study may point to better, more efficient ways to address these symptoms. However, it is also known that lithium does little for, if not worsens, cognitive symptoms in patients (Pachet and Wisniewski, 2003), and it is this symptom domain that is in dire need of drug development.

It is also important to keep in mind that acute silencing of Disc1 in a restricted set of cells will not necessarily recapitulate the pathogenetic process of a disease-associated mutation. It remains to be seen if similar results are obtained in animal models of the Disc1 mutation (Clapcote et al., 2007; Hikida et al., 2007; Li et al., 2007).

References:

Kamiya A, Kubo K, Tomoda T, Takaki M, Youn R, Ozeki Y, Sawamura N, Park U, Kudo C, Okawa M, Ross CA, Hatten ME, Nakajima K, Sawa A. A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development. Nat Cell Biol. 2005 Dec 1;7(12):1167-78. Abstract

Santarelli, L. et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301, 805–809 (2003). Abstract

Airan, R.D. et al. High-speed imaging reveals neurophysiological links to behavior in an animal model of depression. Science 317, 819-23 (2007). Abstract

Pachet AK, Wisniewski AM. The effects of lithium on cognition: an updated review. Psychopharmacology (Berl). 2003 Nov;170(3):225-34. Review. Abstract

Clapcote SJ, Lipina TV, Millar JK, Mackie S, Christie S, et al. (2007) Behavioral phenotypes of Disc1 missense mutations in mice. Neuron 54: 387–402. Abstract

Hikida T, Jaaro-Peled H, Seshadri S, Oishi K, Hookway C, et al. (2007) Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans. Proc Natl Acad Sci U S A 104: 14501–14506. Abstract

Li W, Zhou Y, Jentsch JD, Brown RA, Tian X, et al. (2007) Specific developmental disruption of disrupted-in-schizophrenia-1 function results in schizophrenia-related phenotypes in mice. Proc Natl Acad Sci U S A 104: 18280–18285. Abstract

View all comments by Khaled Rahman

Related News: DISC1: A Matter of Life or Death for Neural Progenitors

Comment by:  Simon Lovestone
Submitted 27 March 2009
Posted 27 March 2009

This is an intriguing paper that builds on a growing body of evidence implicating wnt regulation of GSK3 signaling in psychotic illness (Lovestone et al., 2007).

It is interesting that the authors report that binding of DISC1 to GSK3 results in no change in the inhibitory Ser9 phosphorylation site of GSK3 but a change in Y216 activation site and that this resulted in effects on some but not all GSK3 substrates. This poses a challenge both in terms of understanding the role of GSK3 signaling in schizophrenia and other psychotic disorders and in drug discovery.

The authors cite some of the other evidence for regulation of GSK3 signaling in psychosis, including, for example, the evidence for a role of AKT signaling alteration in schizophrenia and lithium, an inhibitor of GSK3, as a treatment for bipolar disorder. But in both cases, AKT (Cross et al., 1995) and lithium (Jope, 2003), the effect on GSK3 is predominantly via Ser9 phosphorylation and not via Y216. The unstated implication is at least two, possibly three, mechanisms for regulation of GSK3 are all involved in psychotic illness—the auto-phosphorylation at Y216, the exogenous signal transduction regulated Ser9 site inhibition and, if the association of schizophrenia with the wnt inhibitor DKK4 we reported is true (Proitsi et al., 2008), also via the wnt signaling effects on disruption of the macromolecular complex that brings GSK3 together with β-catenin. On the one hand, this might be taken as positive evidence of a role for GSK3 in psychosis—all of its regulatory mechanisms have been implicated; therefore, the case is stronger. On the other hand, GSK3 lies at the intersection point of very many signaling pathways and so is likely to be implicated in many disorders (as it is), and the fact that in cellular and animal models related to psychosis there is no consistent effect on the enzyme is troublesome.

From a drug discovery perspective, those with GSK3 inhibitors in the pipeline will be watching this space carefully. However, it is worth noting that Mao et al. find very selective effects of DISC1 on GSK3 substrates. Despite convincing evidence of an increase in Y216 phosphorylation, which one would expect to increase activity of GSK3 against all substrates, the authors find no evidence of effects on phosphorylation of the GSK3 substrates Ngn2 or C/EBPα. This is somewhat puzzling and merits further attention, especially as in vitro direct binding of a DISC1 fragment to GSK3 inhibited the action of GSK3 on a range of substrates. Might there be more to the direct interaction of DISC1 with GSK3 than a regulation of Y216 autophosphorylation and activation? If, however, GSK3 regulation turns out to be part of the mechanism of schizophrenia or bipolar disorder, then identifying which of the substrates and which of the many activities of GSK3, including on plasticity and hence cognition (Peineau et al., 2007; Hooper et al., 2007), are important in disease will become the critical task.

References:

Lovestone S, Killick R, Di Forti M, Murray R. Schizophrenia as a GSK-3 dysregulation disorder. Trends Neurosci. 2007 Apr 1 ; 30(4):142-9. Abstract

Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature . 1995 Dec 21-28 ; 378(6559):785-9. Abstract

Jope RS. Lithium and GSK-3: one inhibitor, two inhibitory actions, multiple outcomes. Trends Pharmacol Sci . 2003 Sep 1 ; 24(9):441-3. Abstract

Proitsi P, Li T, Hamilton G, Di Forti M, Collier D, Killick R, Chen R, Sham P, Murray R, Powell J, Lovestone S. Positional pathway screen of wnt signaling genes in schizophrenia: association with DKK4. Biol Psychiatry . 2008 Jan 1 ; 63(1):13-6. Abstract

Peineau S, Taghibiglou C, Bradley C, Wong TP, Liu L, Lu J, Lo E, Wu D, Saule E, Bouschet T, Matthews P, Isaac JT, Bortolotto ZA, Wang YT, Collingridge GL. LTP inhibits LTD in the hippocampus via regulation of GSK3beta. Neuron . 2007 Mar 1 ; 53(5):703-17. Abstract

Hooper C, Markevich V, Plattner F, Killick R, Schofield E, Engel T, Hernandez F, Anderton B, Rosenblum K, Bliss T, Cooke SF, Avila J, Lucas JJ, Giese KP, Stephenson J, Lovestone S. Glycogen synthase kinase-3 inhibition is integral to long-term potentiation. Eur J Neurosci . 2007 Jan 1 ; 25(1):81-6. Abstract

View all comments by Simon Lovestone

Related News: DISC1: A Matter of Life or Death for Neural Progenitors

Comment by:  Nick Brandon (Disclosure)
Submitted 27 March 2009
Posted 30 March 2009
  I recommend the Primary Papers

Li-huei Tsai and colleagues have identified another pathway in which the candidate gene DISC1 looks to have a critical regulatory role, namely the wnt signaling pathway, in progenitor cell proliferation. In recent years we have seen that DISC1 has a vital role at the centrosome (Kamiya et al., 2005), in cAMP signaling (Millar et al., 2005), and in multiple steps of adult hippocampal neurogenesis (Duan et al., 2007). They have shown a pivotal role for DISC1 in neural progenitor cell proliferation through regulation of GSK3 signaling using a spectacular combination of cellular and in utero manipulations with shRNAs and GSK3 inhibitor compounds. These findings clearly implicate DISC1 in another “druggable” pathway but at this stage do not really identify new approach/targets, except perhaps to confirm that manipulating adult neurogenesis and the wnt pathway holds much potential hope for therapeutics. Perhaps understanding the mechanism of inhibition of GSK3 by DISC1 in more detail might reveal more novel approaches or encourage more innovative work around this pathway. In addition, I have read the other comment (by Rahman), and though I agree that this work still leaves many questions to be answered, the paper is much more significant and likely reconcilable with previous papers than appreciated. The commentary from Lovestone was very insightful and brings up additional gaps and issues with the present work. Additional experimentation I am sure will tease out more key facets of the DISC1-wnt interaction in the near future.

There are many avenues now to proceed with this work. In particular, from the DISC1-centric view, a GSK3 binding site on DISC1 overlaps with one of the critical core PDE4 binding site. Mao et al. show that residues 211 to 225 are a core part of a GSK3 binding site. Previously, Miles Houslay had shown very elegantly that residues 191-230 form a common binding site (known as common site 1) for both PDE4B and 4D families (Murdoch et al., 2007). It will be important to understand the relationship between GSK3 and PDE4 related signaling in reference to the activity of DISC1 starting at whether a trimolecular complex among DISC1-PDE4-GSK3 can form. Then it will be critical to understand the regulatory interplay among these molecules. For example, it is known that PKA can regulate GSK3 activity (Torii et al., 2008) and the interaction between DISC1 and PDE4, while both GSK3 and PKA can phosphorylate β-catenin (Taurin et al., 2006). The output of these relationships on progenitor proliferation will further deepen insights into the role of DISC1 complexes in neuronal processes. This type of situation is not really surprising for a molecule (DISC1) which has been shown to interact with >100 proteins (Camargo et al., 2007). The context of these interactions in both normal development and disease is likely to be critical to allow understanding of its complete functional repertoire.

Another area where these new findings need to be exploited is in the study of additional animal models. Though the two behavioral endpoint models used in the paper (amphetamine hyperactivity and forced swim test) provide a tantalizing glimpse of the behavioral importance of the complex, it would be critical to look in additional models relevant for schizophrenia and mood disorders. Furthermore, it will be very interesting to look at the effects of GSK3β inhibitors in some of the DISC1 animal models already available and to see if they can reverse all or a subset of reported behaviors. In reviewing a summary of the phenotypes available to date (Shen et al., 2008) there is clearly a number of lines which share the properties with mice injected with DISC1 shRNA into the dentate gyrus and would be of value to look at.

A very exciting paper which I am sure will drive additional research into understanding the role of DISC1 in psychiatry and hopefully encourage drug discovery efforts around this molecular pathway (Wang et al., 2008).

References:

1. Kamiya A, Kubo K, Tomoda T, Takaki M, Youn R, Ozeki Y, Sawamura N, Park U, Kudo C, Okawa M, Ross CA, Hatten ME, Nakajima K, Sawa A. A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development. Nat Cell Biol . 2005 Dec 1 ; 7(12):1167-78. Abstract

2. Millar JK, Pickard BS, Mackie S, James R, Christie S, Buchanan SR, Malloy MP, Chubb JE, Huston E, Baillie GS, Thomson PA, Hill EV, Brandon NJ, Rain JC, Camargo LM, Whiting PJ, Houslay MD, Blackwood DH, Muir WJ, Porteous DJ. DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science . 2005 Nov 18 ; 310(5751):1187-91. Abstract

3. Duan X, Chang JH, Ge S, Faulkner RL, Kim JY, Kitabatake Y, Liu XB, Yang CH, Jordan JD, Ma DK, Liu CY, Ganesan S, Cheng HJ, Ming GL, Lu B, Song H. Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell . 2007 Sep 21 ; 130(6):1146-58. Abstract

4. Murdoch H, Mackie S, Collins DM, Hill EV, Bolger GB, Klussmann E, Porteous DJ, Millar JK, Houslay MD. Isoform-selective susceptibility of DISC1/phosphodiesterase-4 complexes to dissociation by elevated intracellular cAMP levels. J Neurosci . 2007 Aug 29 ; 27(35):9513-24. Abstract

5. Torii K, Nishizawa K, Kawasaki A, Yamashita Y, Katada M, Ito M, Nishimoto I, Terashita K, Aiso S, Matsuoka M. Anti-apoptotic action of Wnt5a in dermal fibroblasts is mediated by the PKA signaling pathways. Cell Signal . 2008 Jul 1 ; 20(7):1256-66. Abstract

6. Taurin S, Sandbo N, Qin Y, Browning D, Dulin NO. Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase. J Biol Chem . 2006 Apr 14 ; 281(15):9971-6. Abstract

7. Camargo LM, Collura V, Rain JC, Mizuguchi K, Hermjakob H, Kerrien S, Bonnert TP, Whiting PJ, Brandon NJ. Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia. Mol Psychiatry . 2007 Jan 1 ; 12(1):74-86. Abstract

8. Shen S, Lang B, Nakamoto C, Zhang F, Pu J, Kuan SL, Chatzi C, He S, Mackie I, Brandon NJ, Marquis KL, Day M, Hurko O, McCaig CD, Riedel G, St Clair D. Schizophrenia-related neural and behavioral phenotypes in transgenic mice expressing truncated Disc1. J Neurosci . 2008 Oct 22 ; 28(43):10893-904. Abstract

9. Wang Q, Jaaro-Peled H, Sawa A, Brandon NJ. How has DISC1 enabled drug discovery? Mol Cell Neurosci . 2008 Feb 1 ; 37(2):187-95. Abstract

View all comments by Nick Brandon

Related News: DISC1: A Matter of Life or Death for Neural Progenitors

Comment by:  Akira Sawa, SRF Advisor
Submitted 8 April 2009
Posted 8 April 2009

Mao and colleagues’ present outstanding work sheds light on a novel function of DISC1. Because DISC1 is a multifunctional protein, the addition of new functions is not surprising. Thus, for the past several years, the field has focused on how DISC1 can have distinct functions in different cell contexts (for example, progenitor cells vs. postmitotic neurons, or developing cortex vs. adult dentate gyrus). In addition to Mao and colleagues, I understand that several groups, including ours, have obtained preliminary, unpublished evidence that DISC1 regulates progenitor cell proliferation, at least in part via GSK3β. Thus, I am very supportive of this new observation.

If there might be a missing point in this paper, it is unclear whether suppression of GSK3β occurs in several different biological contexts in brain in vivo. In other words, it is uncertain whether DISC1’s actions on GSK3β are constitutive or context-dependent. How can we reconcile differential roles for DISC1 in progenitor cells in contrast to postmitotic neurons? We have already obtained a preliminary promising answer to this question, which is currently being validated very intensively. These two phenotypes (progenitor cell control and postmitotic migration) may compensate for each other in cortical development; thus, overall cortical pathology looks milder in adults, at least in our preliminary unpublished data using DISC1 knockout mice. We are not sure how this novel function of DISC1 may account for the pathology of Scottish cases. Although I have great respect for the Scottish pioneers of DISC1 study, such as St. Clair, Blackwood, and Muir (I believe that the St. Clair et al., 1990 Lancet paper is one of the best publications in psychiatry), now is the time to pay more and more attention to the question of the molecular pathway(s) involving DISC1 in general schizophrenia (see 2009 SRF roundtable discussion). Unlike the role of APP in Alzheimer’s disease, DISC1 is not a key biological target in general schizophrenia, instead being an entry point to explore much more important targets for schizophrenia. There may be no more need to stick to DISC1 itself in the unique Scottish cases in schizophrenia research. In sum, although there may still be key missing points in this study, I wish to congratulate the authors on their outstanding work.

References:

St Clair D, Blackwood D, Muir W, Carothers A, Walker M, Spowart G, Gosden C, Evans HJ. Association within a family of a balanced autosomal translocation with major mental illness. Lancet . 1990 Jul 7 ; 336(8706):13-6. Abstract

View all comments by Akira Sawa

Related News: Dynamic Duo: DISC1 and Dixdc1 Team Up to Regulate Brain Development

Comment by:  Kevin J. Mitchell
Submitted 19 July 2010
Posted 19 July 2010

The paper by Singh and colleagues adds to the growing list of proteins that interact with DISC1 and deepens our understanding of the biochemical pathways through which DISC1 modulates various neurodevelopmental processes. They demonstrate that the Dixdc1 protein interacts biochemically with DISC1, and that it functions together with DISC1 in two separable processes: neuronal proliferation and migration.

Interestingly, the nature of the interaction between Dixdc1 and DISC1 differs in these two processes. Knockdown of either Dixdc1 or DISC1 reduces proliferation, but the effects of knocking both down together are additive, indicating the absence of any epistatic interaction. Moreover, the effects of knockdown of either gene alone can be rescued by overexpressing the other gene. This suggests a partial redundancy in their functions rather than an intimate relationship where they necessarily work together.

Knockdown of either gene also disrupts neuronal migration in the cortex, but in this case the defects cannot be rescued by overexpression of the other gene, suggesting they may work more closely together in this context. These genes also act in distinct biochemical pathways in each context—through the Wnt/β-catenin pathway in proliferation and through a Cdk5-modulated Ndel1 pathway in cell migration, which impinges on the cytoskeleton.

These findings have several implications for the ongoing quest to understand the pathogenic mechanisms by which disruption of DISC1 pathways can result in psychiatric disease. First, as with PDE4B, NDE1, and PCM1, for example, they provide—through guilt by association—another viable candidate gene, Dixdc1, that may be analyzed for mutations in upcoming whole-genome sequencing efforts. More importantly, perhaps, they provide the means to dissociate the various functions of DISC1 during neurodevelopment.

One of the major difficulties in moving from gene identification to pathogenic mechanism has been that many of the genes with mutations linked to schizophrenia have highly pleiotropic effects; they play roles in many different processes, any one of which, or all of which together, might be responsible for the pathogenic effects. By dissecting the biochemical pathways mediating the different cellular functions of genes like DISC1, we can hope to develop animal models that can dissociate these functions and begin to dissect their contributions to pathogenesis.

View all comments by Kevin J. Mitchell

Related News: Dynamic Duo: DISC1 and Dixdc1 Team Up to Regulate Brain Development

Comment by:  David J. Porteous, SRF Advisor
Submitted 21 July 2010
Posted 21 July 2010

The high prevalence of schizophrenia and related major mental illness, including bipolar disorder, in the Scottish family with the chromosome 1;11 translocation told us that the breakpoint gene DISC1 was an important key to unlocking the door on the molecular mechanisms underlying psychiatric illness (Millar et al., 2000; Blackwood et al., 2001). And so it has turned out to be (see review by Chubb et al., 2008). DISC1 is a scaffold protein that binds to and regulates other proteins critical in neurodevelopment and neurosignaling. We know the identity of several DISC1 interactors—PDE4, NDE1, NDEL1, PCM1, and Girdin amongst them—but at every turn, a new interactor seems to turn up.

Just last year, Li-Huei Tsai’s group identified GSK3β as a fascinating addition to the pantheon (Mao et al., 2009). GSK3β is interesting on two major counts: first, for its role in Wnt signalling and neuronal transcription; second, as a target for the action of lithium, the front-line treatment for bipolar disorder. Now, her group reports on another novel DISC1 interactor, Dixdc1. I won’t attempt to summarize the whole story—see the SRF news story for more background and details and then seek out the original for the full story—but hers is a “must-read” study. The key points are that 1) Dixdc1 is a novel and potent DISC1 interactor; 2) Dixdc1, like DISC1, modulates GSK3β and Wnt signalling; 3) the Wnt pathway regulates neuronal progenitor proliferation; 4) the effects of DISC1 and Dixdc1 are additive and compensatory; 5) the same is true for their effect in neuronal migration, which occurs not through Wnt signaling, but rather through Cdk5-mediated, phosphorylation-dependent tripartite interaction with NDEL1.

This important new work highlights yet again the insights emerging from the DISC1 complex and its manifold consequences. It needs to be integrated with other recent important findings, including the link through Girdin to AKT signalling (Kim et al., 2009; Enomoto et al., 2009), which in turn links back to GSK3β and Wnt signaling. It also connects to other recent work suggesting a convergent link between DISC1 and a second, strong genetic candidate risk factor for major mental illness, NRG1, mediated via Erb2/3 and P13K/AKT (Seshadri et al., 2010) and to glutamatergic neurotransmission (Hayashi-Takagi et al., 2010).

It is worth reflecting whether or how these connections would have been made without the start point of DISC1 as an unambiguous causal link to psychiatric illness (Porteous, 2008). The new study raises important questions about the potential contribution to genetic risk from variation in each of these DISC1 pathway genes (Porteous, 2008; Hennah and Porteous, 2009). It begs the question of which proteins bind DISC1 in developmental time and cellular space and how this all affects neurodevelopment, neurosignaling, and brain circuitry (Porteous and Millar, 2009).

References:

Blackwood DH, Fordyce A, Walker MT, St. Clair DM, Porteous DJ, Muir WJ. Schizophrenia and affective disorders--cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family. Am J Hum Genet. 2001;69:428-33. Abstract

Chubb JE, Bradshaw NJ, Soares DC, Porteous DJ, Millar JK. The DISC locus in psychiatric illness. Mol Psychiatry. 2008;13:36-64. Abstract

Enomoto A, Asai N, Namba T, Wang Y, Kato T, Tanaka M, Tatsumi H, Taya S, Tsuboi D, Kuroda K, Kaneko N, Sawamoto K, Miyamoto R, Jijiwa M, Murakumo Y, Sokabe M, Seki T, Kaibuchi K, Takahashi M. Roles of disrupted-in-schizophrenia 1-interacting protein girdin in postnatal development of the dentate gyrus. Neuron. 2009;63:774-87. Abstract

Hayashi-Takagi A, Takaki M, Graziane N, Seshadri S, Murdoch H, Dunlop AJ, Makino Y, Seshadri AJ, Ishizuka K, Srivastava DP, Xie Z, Baraban JM, Houslay MD, Tomoda T, Brandon NJ, Kamiya A, Yan Z, Penzes P, Sawa A. Disrupted-in-Schizophrenia 1 (DISC1) regulates spines of the glutamate synapse via Rac1. Nat Neurosci. 2010;13:327-32. Abstract

Hennah W, Porteous D. The DISC1 pathway modulates expression of neurodevelopmental, synaptogenic and sensory perception genes. PLoS One. 2009;4:e4906. Abstract

Kim JY, Duan X, Liu CY, Jang MH, Guo JU, Pow-anpongkul N, Kang E, Song H, Ming GL. DISC1 regulates new neuron development in the adult brain via modulation of AKT-mTOR signaling through KIAA1212. Neuron. 2009;63:761-73. Abstract

Mao Y, Ge X, Frank CL, Madison JM, Koehler AN, Doud MK, Tassa C, Berry EM, Soda T, Singh KK, Biechele T, Petryshen TL, Moon RT, Haggarty SJ, Tsai LH. Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling. Cell. 2009;136:1017-31. Abstract

Millar JK, Wilson-Annan JC, Anderson S, Christie S, Taylor MS, Semple CA, Devon RS, St. Clair DM, Muir WJ, Blackwood DH, Porteous DJ. Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet. 2000;9:1415-23. Abstract

Porteous D. Genetic causality in schizophrenia and bipolar disorder: out with the old and in with the new. Curr Opin Genet Dev. 2008;18:229-34. Abstract

Porteous D, Millar K. How DISC1 regulates postnatal brain development: girdin gets in on the AKT. Neuron. 2009;63:711-3. Abstract

Seshadri S, Kamiya A, Yokota Y, Prikulis I, Kano S, Hayashi-Takagi A, Stanco A, Eom TY, Rao S, Ishizuka K, Wong P, Korth C, Anton ES, Sawa A. Disrupted-in-Schizophrenia-1 expression is regulated by beta-site amyloid precursor protein cleaving enzyme-1-neuregulin cascade. Proc Natl Acad Sci U S A. 2010;107:5622-7. Abstract

View all comments by David J. Porteous

Related News: Dynamic Duo: DISC1 and Dixdc1 Team Up to Regulate Brain Development

Comment by:  Fengquan Zhou
Submitted 3 August 2010
Posted 3 August 2010
  I recommend the Primary Papers

Last year, an interesting paper (Mao et al., 2009) demonstrated that DISC1 regulates neurogenesis via directly interacting with and inhibiting GSK3, which subsequently activates the canonical Wnt pathway via stabilization of β-cantenin. Now a paper from the same group has identified a DISC1 binding protein named Dixdc1, which functions together with DISC1 to regulate neurogenesis and neuronal migration.

Specifically, the paper demonstrates that knocking down either DISC1 or Dixdc1 impairs neural progenitor proliferation and the activation of the canonical Wnt pathway, and double knocking down both proteins has an additive effect. In addition, the effects of knockdown of either gene alone can be fully rescued by overexpressing the other gene. These results suggest that DISC1 and Dixdc1 play redundant roles in regulation of neural progenitor cell proliferation via the GSK3-β-catenin pathway. However, disruption of the interaction between the two proteins also decreases the progenitor proliferation and the activation of the GSK3-β-catenin pathway, suggesting that they coordinate with each other. One potential explanation is that either DISC1 or Dixdc1 can function to inhibit GSK3 and activate the canonical Wnt pathway alone but at less efficiency. The formation of the protein complex may help better recruit GSK3 and thus increase the efficiency of GSK3 inhibition. The rescue results are probably due to overexpression of the proteins, which also increases the access to GSK3.

Very interestingly, the paper shows that knocking down either Dixdc1 or DISC1 also impairs neuronal migration. Unlike the effects in neurogenesis, those on neuronal migration cannot be rescued by overexpression of the other gene. In addition, activation of the canonical Wnt pathway via overexpression of a stabilized β-catenin cannot rescue the defect in neuronal migration. Thus, the authors suggest that DISC1 and Dixdc1 coordinate to regulate neuronal migration independent of the GSK3-β-catenin pathway, possibly via Ndel1, a protein known to regulate neuronal migration. As β-catenin is only one of the many substrates of GSK3 and many known substrates of GSK3 are cytoskeletal proteins (Zhou and Snider, 2005), it is possible that DISC1 and Dixdc1 coordinate to regulate neuronal migration via GSK3 signaling, which has recently been shown to regulate neuronal migration (Asada and Sanada, 2010). A unique feature of GSK3 signaling is the importance of its spatial regulation, which may explain the lack of rescuing effect with overexpression of one gene.

GSK3 signaling has recently been shown to play important roles in many neurodevelopmental processes, including neurogenesis, neuronal polarization, and axon outgrowth (Hur and Zhou, 2010). However, how GSK3 activity is regulated in the developing brain is not clear. This study not only identifies a potential regulator of GSK3, but also provides additional evidence that GSK3 signaling may be involved in neuronal migration.

References:

Asada, N., and Sanada, K. (2010). LKB1-mediated spatial control of GSK3beta and adenomatous polyposis coli contributes to centrosomal forward movement and neuronal migration in the developing neocortex. J Neurosci 30, 8852-8865. Abstract

Hur, E.M., and Zhou, F.Q. (2010). GSK3 signalling in neural development. Nat Rev Neurosci 11, 539-551. Abstract

Mao, Y., Ge, X., Frank, C.L., Madison, J.M., Koehler, A.N., Doud, M.K., Tassa, C., Berry, E.M., Soda, T., Singh, K.K., et al. (2009). Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling. Cell 136, 1017-1031. Abstract

Zhou, F.Q., and Snider, W.D. (2005). Cell biology. GSK-3beta and microtubule assembly in axons. Science 308, 211-214. Abstract

View all comments by Fengquan Zhou

Related News: NYAS 2011—New Molecular Targets for Schizophrenia

Comment by:  Jim Woodgett
Submitted 26 April 2011
Posted 27 April 2011

Several of the reports from the NYAS meeting describe the potential role of GSK-3β in DISC1 functions. This is one of two isoforms, and the other, GSK-3α, tends to get short shrift from researchers. This is problematic for several reasons. Firstly, the two isoforms, despite being derived from distinct genes, are essentially identical within their catalytic domains. Consequently, there are no small molecule inhibitors that that are isoform selective, and the two proteins are highly redundant (albeit not completely) in function. Secondly, in the case of DISC1, there are new data indicating a role for GSK-3α in DISC1 functions. Small molecule (isoform indiscriminate) inhibitors of GSK-3 restore behavioral deficits of DISC1 L100P animals, and this is also achieved by genetic inactivation of one allele of GSK-3α (Lipina et al., 2011). Examination of the brains of the DISC1 and DISC1/GSK-3α+/- animals revealed that dendritic spine density deficits observed in DISC1 L100P brains were restored upon deletion of one copy of GSK-3α (Lee et al., 2011).

From a therapeutic point of view, there appears to be no easy way to selectively inhibit only one isoform of GSK-3 (the only means is via RNA interference), so perhaps it is fortunate that both isoforms appear to play similar roles? Birds, on the other hand, appear to have selectively lost GSK-3α, though the consequences in terms of brain development and function are currently unclear (Alon et al., 2011).

References:

Lipina TV, Kaidanovich-Beilin O, Patel S, Wang M, Clapcote SJ, Liu F, Woodgett JR, Roder JC. (2011). Genetic and pharmacological evidence for schizophrenia-related Disc1 interaction with GSK-3. Synapse 65(3):234-48. Abstract

Lee FH, Kaidanovich-Beilin O, Roder JC, Woodgett JR, Wong AH. (2011) Genetic inactivation of GSK3α rescues spine deficits in Disc1-L100P mutant mice. Schizophr Res. Abstract

Alon LT, Pietrokovski S, Barkan S, Avrahami L, Kaidanovich-Beilin O, Woodgett JR, Barnea A, Eldar-Finkelman H. (2011) Selective loss of glycogen synthase kinase-3α in birds reveals distinct roles for GSK-3 isozymes in tau phosphorylation. FEBS Lett. 585(8):1158-62. Abstract

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