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News Brief: Schizophrenia-linked AKT1 Variant Affects Brain Parameters

5 June 2008. More evidence can be added to the file of schizophrenia gene suspect AKT1, according to a new paper by Daniel Weinberger’s group at the U.S. National Institute of Mental Health in Bethesda, Maryland. In their paper, published online May 22 in the Journal of Clinical Investigation, first author Hao-Yang Tan and colleagues employed a multipronged approach (see SRF related news story) to find that a functionally relevant—and schizophrenia-linked—coding variant in the AKT1 gene affects cognition and frontal cortical-striatal structures and signaling, specifically related to dopaminergic neurotransmission (see SRF related news story).

For more details, we are pleased to refer you to the open-access article, as well as a very lucid commentary by Alexander Arquello and Joseph Gogos of Columbia University in New York City.—Hakon Heimer.

References:

Tan HY, Nicodemus KK, Chen Q, Li Z, Brooke JK, Honea R, Kolachana BS, Straub RE, Meyer-Lindenberg A, Sei Y, Mattay VS, Callicott JH, Weinberger DR. Genetic variation in AKT1 is linked to dopamine-associated prefrontal cortical structure and function in humans. J Clin Invest. 2008 May 22. [Epub ahead of print] Abstract

Arguello PA, Gogos JA. A signaling pathway AKTing up in schizophrenia. J Clin Invest. 2008 May 22. [Epub ahead of print] Abstract

Comments on News and Primary Papers
Comment by:  Takeo YoshikawaAkihiko Takashima
Submitted 17 June 2008
Posted 17 June 2008

Some researchers in the field of psychiatric genetics have become somewhat pessimistic about the ability to detect robust genotype-phenotype correlations using the diagnostic criteria defined by DSM-IV. If we analyze tens of thousands of samples, the ensuing results may be statistically robust, but still the effect of common variant(s) of each gene will be modest. Recently, Tan et al. (2008) reported that the AKT1 gene SNP rs1130233 and its encompassing haplotypes are significantly associated with IQ/processing speed, activities that may reflect frontal cortex function. They also showed that performance in their psychological test battery is influenced not only by AKT1 genetic variants but also the well-known COMT gene non-synonymous polymorphism (SNP rs4680, Val158Met). By undertaking fMRI analysis, they intertwined the IQ/processing speed-frontal cortex-AKT1 signal-DA system, i.e., the. integration of multidimensional disciplines. In citing references (Meyer-Lindenberg and Weinberger, 2006; Weinberger et al., 2001), they state that “there is a growing body of data showing that genes weakly associated with complex constellations of behavioral symptoms are much more strongly associated with in vivo brain measures.” Indeed, they have succeeded in explaining a possible role for AKT1 in brain execution capability, but have not provided convincing evidence for genetic associations between AKT1 and schizophrenia.

Their current results are elegantly derived from “a complex set of experiments addressing association of multiple variants in a gene with many phenotypic measures.” However, from a genetic perspective, we may still ask the following questions, irrelevant of the current study:

1. What is the genetic component (or heritability) of each psychological and imaging trait? Can variations in some of the psychological/cognitive/intellectual performances be fully captured by a single gene in an experimental set that examines, at the most, a hundred samples? We have learned the hard way from genetic association studies done in the 1990s, which examined a small number of samples, that we simply cannot trust those results. With regard to this point, the heritability calculations of so-called “endophenotypes” as reported by Greenwood et al. (2007) can give helpful information [also see Watanabe et al., 2007, supplementary Table S2]. There is the possibility that the genetic architecture of neurocognitive functions and imaging measures may not be simpler than the current disease category (entity).

2. Given the rapid advances in genotyping technology, we may be able to generate genome-wide genetic test results for every neuropsychiatric trait in the near future.

3. Because of the functional significance of AKT1 and the divergence in the signaling cascade downstream of AKT1, it would be wise to confine analysis to this gene. However, it is frustrating that we still do not know the functionally important SNP(s) of AKT1 in spite of numerous association studies.

4. Nackley et al. (2006) have convincingly demonstrated that the haplotype of the COMT gene constructed by synonymous SNPs has much more functional impact than the Val158Met polymorphism. Therefore, we would like to see the association studies examining this haplotype in future neuropsychiatric studies.

From a biochemical perspective, the following issues would be interesting and future targets for clarification:

1. The authors suggest that the coding synonymous variation of AKT1 affects protein expression, leading to the alteration of frontostriatal function and gray matter volume. The activity of AKT1 is regulated by its phosphorylation status. Therefore, readers would want to know whether the reduction of AKT1 expression levels actually affect the AKT signaling pathway. Behavioral analysis and an MRI study of Akt1 heterozygote knockout mice may provide relevant information.

2. Impairment of the AKT signal is known to result in tau hyperphosphorylation through activation of GSK3 as seen in Alzheimer disease brains. According to this idea, a reduction of AKT levels caused by SNP(s) should elicit hyperphosphorylation of tau and ultimately form neurofibrillary tangles (NFTs). In contrast, there are some reports suggesting the absence of NFTs and neuroinjury in elderly patients with schizophrenia (Arnold et al., 1998; Purohit et al., 1998). It is also reported that GSK3 is reduced in schizophrenia (Beasley et al., 2001). It would be interesting to know whether the genetic variation(s) of AKT1 that induce decreased protein expression affect tau accumulation.

3. Lithium inhibits the arrestin-Akt signal (Beaulieu et al., 2008). If so, it would be interesting to know whether lithium treatment can restore some of the effects of reduced AKT1 expression levels caused by the SNP(s) of interest.

References:

Arnold SE, Trojanowski JQ, Gur RE, Blackwell P, Han LY, Choi C. Absence of neurodegeneration and neural injury in the cerebral cortex in a sample of elderly patients with schizophrenia. Arch Gen Psychiatry 1998 55:225-232. Abstract

Beasley C, Cotter D, Khan N, Pollard C, Sheppard P, Varndell I, Lovestone S, Anderton B, Everall I. Glycogen synthase kinase-3beta immunoreactivity is reduced in the prefrontal cortex in schizophrenia. Neurosci Lett 2001 302:117-120. Abstract

Beaulieu JM, Marion S, Rodriguiz RM, Medvedev IO, Sotnikova TD, Ghisi V, Wetsel WC, Lefkowitz RJ, Gainetdinov RR, Caron MG.. A beta-arrestin 2 signaling complex mediates lithium action on behavior. Cell 2008 132:125-36. Abstract

Greenwood TA, Braff DL, Light GA, Cadenhead KS, Calkins ME, Dobie DJ, Freedman R, Green MF, Gur RE, Gur RC, Mintz J, Nuechterlein KH, Olincy A, Radant AD, Seidman LJ, Siever LJ, Silverman JM, Stone WS, Swerdlow NR, Tsuang DW, Tsuang MT, Turetsky BI, Schork NJ. Initial heritability analyses of endophenotypic measures for schizophrenia: the consortium on the genetics of schizophrenia. Arch Gen Psychiatry 2007 64:1242-1250. Abstract

Meyer-Lindenberg AS, Weinberger DR: Intermediate phenotypes and genetic mechanisms of psychiatric disorders. Nat Rev Neurosci 2006 7:818-827. Abstract

Nackley AG, Shabalina SA, Tchivileva IE, Satterfield K, Korchynskyi O, Makarov SS, Maixner W, Diatchenko L: Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure. Science 2006 314:1930-1933. Abstract

Purohit DP, Perl DP, Haroutunian V, Powchik P, Davidson M, Davis KL: Alzheimer disease and related neurodegenerative diseases in elderly patients with schizophrenia: a postmortem neuropathologic study of 100 cases. Arch Gen Psychiatry 1998 55:205-211. Abstract

Tan HY, Nicodemus KK, Chen Q, Li Z, Brooke JK, Honea R, Kolachana BS, Straub RE, Meyer-Lindenberg A, Sei Y, Mattay VS, Callicott JH, Weinberger DR: Genetic variation in AKT1 is linked to dopamine-associated prefrontal cortical structure and function in humans. J Clin Invest 2008 118:2200-2208. Abstract

Watanabe A, Toyota T, Owada Y, Hayashi T, Iwayama Y, Matsumata M, Ishitsuka Y, Nakaya A, Maekawa M, Ohnishi T, Arai R, Sakurai K, Yamada K, Kondo H, Hashimoto K, Osumi N, Yoshikawa T: Fabp7 maps to a quantitative trait locus for a schizophrenia endophenotype. PLoS Biology 2007 5:e297. Abstract

Weinberger DR, Egan MF, Bertolino A, Callicott JH, Mattay VS, Lipska BK, Berman KF, Goldberg TE: Prefrontal neurons and the genetics of schizophrenia. Biol Psychiatry 2001 50:825-844. Abstract

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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.

View all comments by Takeo Yoshikawa
View all comments by Akihiko Takashima

Related News: DARPP-32 Haplotype Affects Frontostriatal Cognition and Schizophrenia Risk

Comment by:  Jonathan Burns
Submitted 14 February 2007
Posted 14 February 2007

This study provides hard empirical evidence for the hypothesis that psychosis (and schizophrenia in particular) represents a costly "byproduct" of complex human (social) brain evolution. Interestingly, the activation paradigms in the fMRI study (N-back and emotional face-matching tasks) are both testing social cognition. And the demonstrated changes in frontostriatal connectivity support the hypothesis that schizophrenia is a disorder of evolved intrahemispheric circuits comprising the Social Brain in our species.

I would suggest that further candidates (conferring vulnerability to psychosis) should be sought from amongst those genes known to have played a significant role in human brain evolution.

References:

Burns J. (2007) The Descent of Madness: Evolutionary Origins of Psychosis and the Social Brain. Routledge Press: Hove, Sussex.

Burns J. The social brain hypothesis of schizophrenia. World Psychiatry. 2006 Jun;5(2):77-81. Abstract

Burns JK. Psychosis: a costly by-product of social brain evolution in Homo sapiens. Prog Neuropsychopharmacol Biol Psychiatry. 2006 Jul;30(5):797-814. Epub 2006 Mar 3. Review. Abstract

Burns JK. An evolutionary theory of schizophrenia: cortical connectivity, metarepresentation, and the social brain. Behav Brain Sci. 2004 Dec;27(6):831-55; discussion 855-85. Review. Abstract

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Related News: DARPP-32 Haplotype Affects Frontostriatal Cognition and Schizophrenia Risk

Comment by:  Daniel Durstewitz
Submitted 8 June 2007
Posted 8 June 2007
  I recommend the Primary Papers

The phosphoprotein DARPP-32 occupies a central position in the dopamine-regulated intracellular cascades of cortical and striatal neurons (Greengard et al., 1999). It is a point of convergence for multiple signaling pathways, is differentially affected by D1- vs. D2-class receptor activation, and mainly through inhibition of protein-phosphotase-1 mediates or contributes to a number of the dopaminergic effects on voltage- and ligand-gated ion channels. These, in turn, by regulating intracellular Ca2+ levels, themselves influence phosphorylation of DARPP-32 and thereby interact with dopamine-induced processes.

Given its central, vital role in dopamine-regulated signaling pathways, it is quite surprising that (to my knowledge) only a few studies exist on the implications of DARPP-32 variations for cognitive functions and brain activity. Therefore, this comprehensive series of studies by Meyer-Lindenberg et al. combining human genetics, structural and functional MRI, and behavioral testing represents an important milestone. Meyer-Lindenberg et al. identified different functionally relevant DARPP haplotypes, associated with differential DARPP mRNA activity in postmortem studies, and found that these were linked to significant differences on a number of cognitive tests probing “executive functions,” as well as to differences in putamen volume and activity, and structural and functional covariation between striatal and prefrontal cortical areas. Thereby, they paved the way for detailed investigations of the role of DARPP-32 in human cognition.

Since DARPP-32 is so intricately interwoven into so many intracellular and physiological feedback loops, as with dopamine itself (Durstewitz and Seamans, 2002), mechanistic accounts for the functional involvement of DARPP-32 variations in neural network dynamics may be hard to obtain. “Linear” causal thinking usually breaks down in such complex functional networks constituted of so many interacting positive and negative feedback loops on different time scales. Thus it may still be a while until we gain a deeper, biophysically based understanding of the neural processes that mediate the influence of DARPP variations on cognition, and integrative computational approaches may be required to help resolving these issues. Given the complexity of DARPP-regulated networks, I also would expect that fine-grained behavioral testing and analysis of error types of human subjects on different cognitive tasks may ultimately reveal quite subtle and differential effects of DARPP polymorphisms. Moreover, the effects on neural network dynamics may be such (e.g., changing the temporal organization of spiking patterns) that they may not always be detectable by current neuroimaging methods, meaning that while the most dramatic effects were found on activation and volume of striatum, where DARPP-32 is most abundantly expressed, a significant contribution of other brain areas in DARPP-associated cognitive differences may not be ruled out. Regardless of these difficulties in unraveling the underlying neural mechanisms, the work by Meyer-Lindenberg et al. allows us to tackle the question of how the balance in dopamine-regulated intracellular networks relates to cognition in humans, and points toward the neural structures and interactions most interesting to look at.

View all comments by Daniel Durstewitz

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

References
Sidhu A. and Niznik HB. (2000). Coupling of dopamine receptor subtypes to multiple and diverse G proteins. Int J Devl Neuroscience 18: 669-677. Abstract

Beom SR., Cheong D., Torres G., Caron MG. and Kim KM. (2004). Comparative studies of molecular mechanisms of dopamine D2 and D3 receptors for the activation of extracellular signal-regulated kinase. J Biol Chem. 279: 28304-28314. Abstract

Missale C., Nash R., Robinson SW., Jaber M. and Caron MG. (1998). Dopamine receptors: From structure to function. Physiol Rev. 78: 189-225. Abstract

Perez MF., White FJ. and Hu XT. (2006). Dopamine D2 receptor modulation of K+ channel activity regulates excitability of nucleus accumbens neurons at different membrane potentials. J Neurophysiol. 96: 2217-2228. Abstract

Hernández-López S., Tkatch T., Perez-Garci E., Galarraga E., Bargas J., Hamm H. and Surmeier DJ. (2000). D2 dopamine receptors in striatal medium spiny neurons reduce L-type Ca2+ currents and excitability via a novel PLCbeta1-IP3-calcineurin-signaling cascade. J Neurosci. 20: 8987-8995. Abstract

Terrillon S. and Bouvier M. (2004). Roles of G-protein-coupled receptor dimerization. EMBO Rep. 5: 30-34. Abstract

Ferré S., Agnati LF., Ciruela F., Lluis C., Woods AS., Fuxe K. and Franco R. (2007a). Neurotransmitter receptor heteromers and their integrative role in 'local modules': the striatal spine module. Brain Res Rev. 55: 55-67. Abstract

Kearn CS., Blake-Palmer K., Daniel E., Mackie K. and Glass M. (2005). Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors enhances heterodimer formation: a mechanism for receptor cross-talk? Mol Pharmacol. 67: 1697-1704. Abstract

Rashid AJ., So CH., Kong MM., Furtak T., El-Ghundi M., Cheng R., O'Dowd BF. and George SR. (2007). D1-D2 dopamine receptor heterooligomers with unique pharmacology are coupled to rapid activation of Gq/11 in the striatum. Proc Natl Acad Sci USA 104: 654-659. Abstract

Ferré S., Ciruela F., Quiroz C., Luján R., Popoli P., Cunha RA., Agnati LF., Fuxe K., Woods AS., Lluis C. and Ranco R. (2007b). Adenosine receptor heteromers and their integrative role in striatal function. ScientificWorldJournal 7: 74-85.

Liu Y., Buck DC. and Neve KA. (2008). Novel interaction of the dopamine D2 receptor and the Ca2+ binding protein S100B: role in D2 receptor function. Mol Pharmacol. 74: 371-378. Abstract

Stanwood GD. (2008). Protein-protein interactions and dopamine D2 receptor signaling: a calcium connection. Mol Pharmacol. 74: 317-319. Abstract

Klewe IV., Nielsen SM., Tarpø L., Urizar E., Dipace C., Javitch JA., Gether U., Egebjerg J. and Christensen KV. (2008). Recruitment of beta-arrestin2 to the dopamine D2 receptor: insights into anti-psychotic and anti-parkinsonian drug receptor signaling. Neuropharmacology 54: 1215-1222. Abstract

Lan H., Teeter MM., Gurevich VV. and Neve KA. (2008a). An intracellular loop2 amino acid residue determines differential binding of arrestin to the dopamine D2 and D3 receptors. Mol Pharmacol. Abstract

Lan H., Liu Y., Bell MI., Gurevich VV. and Neve KA. (2008b). A dopamine D2 receptor mutant capable of G protein-mediated signaling but deficient in arrestin binding. Mol Pharmacol. Abstract

Arguello PA. and Gogos JA. (2008). A signaling pathway AKTing up in schizophrenia. J Clin Invest. 118: 2018-2021. Abstract

Beaulieu JM., Sotnikova TD., Marion S., Lefkowitz RJ., Gainetdinov RR. and Caron MG. (2005). An Akt/beta-Arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. Cell 122: 261-273. Abstract

Brazil DP. and Hemmings BA. (2001). Ten years of protein kinase B signaling: a hard Akt to follow. Trends Biochem Sci. 26: 657-664. Abstract

Brazil DP., Yang ZZ. and Hemmings BA. (2004). Advances in protein kinase B signaling: AKTion on multiple fronts. Trends Biochem Sci. 29: 233-242. Abstract

Emamian ES., Hall D., Birnbaum MJ., Karayiorgou M. and Gogos JA. (2004). Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nat Genet. 36: 131-137. Abstract

Kalkman HO. (2006). The role of the phosphoinositide 3-kinase-protein kinase B pathway in schizophrenia. Pharmacol Ther. 110: 117-134. Abstract

Beaulieu JM., Gainetdinov RR. and Caron MG. (2007a). The Akt-GSK-3 signaling cascade in the actions of dopamine. Trends Pharmacol Sci. 28: 166-172. Abstract

Beaulieu JM., Tirotta E., Sotnikova TD., Masri B, Salahpour A., Gainetdinov RR., Borrelli E. and Caron MG. (2007b). Regulation of Akt signaling by D2 and D3 dopamine receptors in vivo. J Neurosci. 27: 881-885. Abstract

Beaulieu JM., Marion S., Rodriguiz RM., Medvedev IO., Sotnikova TD., Ghisi V., Wetsel WC., Lefkowitz RJ., Gainetdinov RR. and Caron MG. (2008). A beta-arrestin 2 signaling complex mediates lithium action on behavior. Cell 132: 125-136. Abstract

Masri B., Salahpour A., Didrikson M., Ghisi V., Beaulieu JM., Gainetdinov RR. and Caron MG. (2008). Antagonism of dopamine D2 receptors/beta-arrestin 2 interaction is a common property of clinically effective antipsychotics. Proc Natl Acad Sci USA 105: 13656-13661. Abstract

Mailman RB. (2007). GPCR functional selectivity has therapeutic impact. Trends Pharmacol Sci. 28: 390-396. Abstract

Urban JD., Vargas GA., von Zastrow M. and Mailman RB. (2007). Aripiprazole has functionally selective actions at dopamine D2 receptor-mediated signaling pathways. Neuropsychopharmacology 32: 67-77. Abstract

Sarbassov DD., Guertin DA., Ali SM. and Sabatini DM. (2005). Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307: 1098-1101. Abstract

Beaulieu JM., Sotnikova TD., Yao WD., Kockeritz L., Woodgett JR., Gainetdinov RR. and Caron MG. (2004). Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade. Proc Natl Acad Sci USA 101: 5099-5104. Abstract

Lovestone S., Killick R., Forti MD. and Murray R. (2007). Schizophrenia as a GSK-3 dysregulation disorder. Trends Neurosci. 30: 142-149. Abstract

Gould TD., Einat H., Bhat R. and Manji H. (2004). AR-A014418, a selective GSK-3 inhibitor, produces antidepressant-like effects in the forced swim test. Int J Neuropsychopharmacol. 7: 387-390. Abstract

Kang UG., Seo MS., Roh MS., Kim Y., Yoon SC. and Kim YS. (2004). The effects of clozapine on the GSK-3-mediated signaling pathway. FEBS Lett. 560: 115-119. Abstract

Sutton LP., Honardoust D., Mouyal J., Rajakumar N. and Rushlow WJ. (2007). Activation of the canonical Wnt pathway by the antipsychotics haloperidol and clozapine involves disheveled-3. J Neurochem. 102: 153-169. Abstract

Roh MS., Seo MS., Kim Y., Kim SH., Jeon WJ., Ahn YM., Kang UG., Juhnn YS. and Kim YS. (2007). Haloperidol and clozapine differentially regulate signals upstream of glycogen synthase kinase 3 in the rat frontal cortex. Exp Mol Med. 39: 353-360. Abstract

Kane JM, Honigfeld G, Singer J, Meltzer H. (1988). Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry. 45: 789-796. Abstract

Tollefson GD, Sanger TM. (1997). Negative symptoms: a path analytic approach to a double-blind, placebo- and haloperidol-controlled clinical trial with olanzapine. Am J Psychiatry. 154: 466-74. Abstract

Keefe RS, Silva SG, Perkins DO, Lieberman JA. (1999). The effects of atypical antipsychotic drugs on neurocognitive impairment in schizophrenia: a review and meta-analysis. Schizophr Bull. 25: 201-22. Abstract

Csernansky JG, Mahmoud R, Brenner R. (2002). A comparison of risperidone and haloperidol for the prevention of relapse in patients with schizophrenia. N Engl J Med. 346: 16-22. Abstract

Wahlbeck K, Tuunainen A, Ahokas A, Leucht S. (2001). Dropout rates in randomised antipsychotic drug trials. Psychopharmacology (Berl). 155: 230-3. Abstract

Lieberman JA, Greenhouse J, Hamer RM, Krishnan KR, Nemeroff CB, Sheehan DV, Thase ME, Keller MB. (2005a). Comparing the effects of antidepressants: consensus guidelines for evaluating quantitative reviews of antidepressant efficacy. Neuropsychopharmacology. 30(3): 445-460. Abstract

Geddes J, Freemantle N, Harrison P, Bebbington P. (2000). Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis. British Medical Journal. 321: 1371-1376. Abstract

Lieberman JA, Stroup S, McEvoy J, Marvin Swartz, Rosenheck R, Perkins D, Keefe RSE, Davis S, Davis CE, Hsiao J, Severe J Lebowitz B, for the CATIE Investigators. (2005b). Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia: Primary Efficacy and Safety Outcomes of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial. N Engl J Med. 353 (12): 1209-1223. Abstract

Jones PB, Barnes TRE, Davies L, Dunn G, Lloyd H, Hayhurst KP, Murray RM, Markwick A, Lewis SW. (2006). Randomized controlled trial of effect on quality of life of second generation versus first generation antipsychotic drugs in schizophrenia—CUtLASS1. Arch Gen Psychiatry. 63: 1079-1087. Abstract

Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. (2008). Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Abstract

Leucht S, Pitschel-Walz G, Abraham D, Kissling W. (1999). Efficacy and extrapyramidal side-effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo. A meta-analysis of randomized controlled trials. Schizophr Res. 35: 51-68. Abstract

Allison DB, Mentore JL, Heo M, et al. (1999). Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry. 156: 1686-96. Abstract

Henderson DC, Cagliero E, Copeland PM, et al. (2005). Glucose metabolism in patients with schizophrenia treated with atypical antipsychotic agents: a frequently sampled intravenous glucose tolerance test and minimal model analysis. Arch Gen Psychiatry. 62: 19-28. Abstract

Kinon BJ, Lieberman JA. (1996). Mechanism of action of atypical antipsychotic drugs: a critical analysis. Psychopharmacology. 124(1/2): 2-34. Abstract

Miyamoto S, Duncan GE, Marx CE, Lieberman JA. (2005). Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol Psychiatry. 10: 79-104. Abstract

Lieberman JA. (2006). Comparative Effectiveness of Antipsychotic Drugs: A commentary on the cost utility of the latest antipsychotic drugs in schizophrenia study (CUtLASS 1) and clinical antipsychotic trials of intervention effectiveness (CATIE). Archives of General Psychiatry. 63: 1069-1072. Abstract

Lewis S and Lieberman JA. (2008). CATIE and CUtLASS: can we handle the truth? Br. J. Psychiatry. 192(3): 161-163. Abstract

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