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NYAS 2011—New Molecular Targets for Schizophrenia

29 March 2011. During the second day of talks at the NYAS meeting on Advancing Drug Discovery in Schizophrenia on 11 March 2011, researchers knuckled down to assess targets for treatment. Jeffrey Lieberman of Columbia University set the stage with an overview of current approaches, which include manipulations of neurotransmitter receptor function or intracellular signaling pathways. There would be no "magic bullet" that would treat all three symptom domains of schizophrenia, he said. Instead, he proposed that research should find adjunctive therapies to treat negative and cognitive symptoms, which likely stem from problems different from those underlying positive symptoms. Because antipsychotics already treat positive symptoms with some success, the challenge will be to find adjunctive therapies that won't undermine the benefits of other drugs.

Lieberman also noted that outcomes are better when psychosis is treated early with antipsychotics, and that early treatment may prevent brain changes that are associated with the worsening of symptoms and cognitive deterioration (Lieberman, 2006). He proposed that brain changes may precede changes in behavior, and that they may make good targets for treatment. In support of this idea, he cited a study that found abnormal fMRI signals in the hippocampus in individuals at risk for schizophrenia that predicted progression to psychosis (see SRF related news story).

From ideas…
Jeffrey Conn of Vanderbilt University described his work looking for ways to boost metabotropic glutamate receptor (mGluR) function—particularly that of mGluR5. Tightly associated with and spurring activity in NMDA receptors, mGluR5 provides a backdoor to normalizing NMDA function, which is hypothesized to be underactive in schizophrenia (see SRF hypothesis). Going after selective agonists for the mGluR5 receptor has been stymied by a highly conserved binding site across all metabotropic receptors. As an alternative, Conn has been developing positive allosteric modulators (PAMs) for mGluR5, which bind a different site than the agonist but still promote mGluR5 responses to endogenous glutamate. He described one in detail, a potent and selective mGluR5 PAM that nearly doubles activity of the receptor when it is bound by an agonist. The compound had antipsychotic-like effects in mice, reversing their amphetamine-induced hyperlocomotion and disruption in prepulse inhibition, and improved performance of mice in the Morris water maze, a test of spatial learning (Ayala et al., 2009). Before moving cousins of this particular PAM into the clinic, Conn emphasized the need to fully characterize them, because subtle changes to their structure can alter their mode of action.

Shifting from receptors to intracellular signaling pathways, Stephen Haggarty of Harvard University and the Broad Institute discussed inhibition of glycogen synthase kinase β (GSK3β) as a strategy for treating psychiatric illness. At a nexus of molecular pathways implicated in schizophrenia and bipolar disorder, GSK3β is an enzyme whose numerous interactions suggest it plays multiple roles in development and in the adult nervous system. It has come to the fore in schizophrenia research through studies that find it is suppressed by the mood stabilizer, lithium (see SRF related news story), by antipsychotics (see SRF related news story), and most recently, by DISC1 (see SZGene entry and Mao et al., 2009). Taking a cue from this theme of GSK3β inhibition, Haggarty described a novel compound that is a selective inhibitor of GSK3β in brain, and also had antimanic and antidepressant-like effects in mice (Pan et al., 2011).

Using small molecule microarray screens to probe the ability of 12,000 compounds to bind to DISC1 variants, Haggarty reaped 383 hits which either activated or attenuated GSK3β activity through DISC1. Stressing the need to characterize these compounds in human neurons to more accurately model how they act in the brain, he described his success in deriving neurons from induced pluripotent stem cells (iPSCs) developed from human skin cells, saying, "We can grow buckets of these." Applying a GSKβ inhibitor to these neurons increased activity in signaling molecules downstream from GSK3β, consistent with suppression of GSK3β.

…to clinical trials
Amanda Law of the National Institute of Mental Health covered a different part of the GSK3β signaling network: the PI3K/AKT pathway. Aberrations in this pathway are suspected in schizophrenia because genetic studies have pointed to variants in the neuregulin gene (see SZGene entry) and its receptor ErbB4 (see SZGene entry), which act upon the PI3K/AKT pathway. AKT, in turn, inhibits GSK3β. To probe the integrity of this pathway in disease, Law used human lymphoblastoid cell lines from controls and people with schizophrenia, saying, "They give you the genetic architecture of a real person."

She reported abnormal upregulation of an isoform of ErbB4, called CYT-1, and an isoform of PI3K called PI3KCD, in schizophrenia and in people homozygous for the risk allele for ErbB4. These upregulations are also found in postmortem brains from people with schizophrenia. Elevated levels of PI3KCD suppress AKT activity, which disinhibits GSK3β and ultimately attenuates neuregulin signaling. This means selective PI3KCD inhibitors may normalize activity in this pathway, and cancer research—which is interested in GSK3β because of its role in cell proliferation—has already come up with some. One that has been tested prevents amphetamine-induced hyperlocomotion in mice, without effects on cognition. PI3KCD inhibitors are in clinical trials already, and these results may establish a place for PI3KCD in the network of schizophrenia-related molecules.

Returning to the idea that underactive NMDA receptors may be at the heart of schizophrenia, Brian Campbell of Pfizer presented a way to suppress kynurenic acid levels in the brain, which are elevated in the CSF in schizophrenia. Kynurenic acid antagonizes NMDA receptors, and abnormally high levels may contribute to cognitive deficits found in schizophrenia. Campbell targeted the key enzyme that makes kynurenic acid in the brain, called kynurenine aminotransferase II (KAT II), with a compound that potently and selectively inhibits KAT II. This KAT II inhibitor reduced kynurenic acid levels by as much as 80 percent in rats and improved performance of rats and nonhuman primates in tasks measuring attention and working memory. It also rapidly reversed anhedonia, as measured by a decrease in sucrose consumption, that resulted from subjecting rats to chronic, mild stress. However, this KAT II inhibitor did not affect the usual models of psychosis-like behavior, like prepulse inhibition or amphetamine-induced hyperlocomotion. This suggests that KAT II inhibitors could work as an adjunctive to antipsychotics to treat cognitive and negative symptoms. Campbell said that the KAT II inhibitor did not interfere with the antipsychotic's ability to normalize psychosis-related measures, but that it was still unclear whether an antipsychotic would undermine the KAT II inhibitor's effect on cognitive measures.—Michele Solis.

Comments on News and Primary Papers
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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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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