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Associative learning and the genetics of schizophrenia
Review
Associative learning and the genetics of schizophrenia Jeremy Hall1, Liana Romaniuk1, Andrew M. McIntosh1, J. Douglas Steele2, Eve C. Johnstone1 and Stephen M. Lawrie1 1 2
Division of Psychiatry, University of Edinburgh, Edinburgh, EH10 5HF, UK Section of Psychiatry and Behavioural Sciences, University of Dundee, Dundee, DD1 9SY, UK
Several well-validated susceptibility genes for schizophrenia have now been identified. We suggest that these genes can be divided into two broad classes. Those in the first class have direct effects on synaptic plasticity mediated through actions at glutamatergic synapses; those in the second class impact on meso-limbic dopamine signalling. We argue that these genes have an interactive effect on risk for psychosis and that this interaction can be understood in the context of associative learning theory. We illustrate how genetic variation in genes from these classes can contribute to the development of psychosis using data from the Edinburgh High Risk Study of schizophrenia. Introduction Recent advances in genetics have led to the identification of several well-supported susceptibility genes for schizophrenia [1,2]. These genes have an apparently disparate range of functions, raising questions about the mechanisms through which they contribute to the development of psychosis (see Glossary). Previous authors have noted a convergence on glutamatergic and dopaminergic pathways [1– 3]. This has led to the suggestion that genes associated with schizophrenia might have a common impact on molecular processes involved in associative learning [3,4]. If this is the case, associative learning theory can provide a framework for understanding how genetic variation in susceptibility genes causes increased risk for psychosis [3–5]. In this article we first outline some key processes in associative learning before reviewing the evidence that such processes are abnormal in schizophrenia. We discuss the evidence that schizophrenia susceptibility genes impact on molecular processes involved in associative learning, focusing on neuregulin-1 (NRG1) and catecholO-methyl transferase (COMT) as examples. Finally, we examine how functional genetic variation can contribute to the development of psychosis using data from our own work in the Edinburgh High Risk Study of schizophrenia (EHRS). Overall, we aim to link the functions of schizophrenia susceptibility genes to potential mechanisms underlying the development of psychotic symptoms. Key concepts in associative learning Associative learning has been extensively studied using classical (Pavlovian) and instrumental conditioning tasks.
A full discussion of associative learning theory is beyond the scope of this review [6]. Instead, we consider some fundamental features of associative learning that are of relevance to the actions of schizophrenia susceptibility genes, focusing on classical conditioning. Classical conditioning is the process by which an initially neutral stimulus (the conditioned stimulus [CS]), by virtue of presentation with a biologically important event (the unconditioned stimulus [US]), comes itself to elicit a characteristic response (the conditioned response [CR]). This CR often resembles the response produced by the presentation of the US alone, known as the unconditioned response (UR). This form of learning can be understood in terms of associative synaptic plasticity, demonstrated electrophysiologically as long-term potentiation (LTP). The properties of the N-methyl-D-aspartic acid (NMDA) glutamate receptor provide a molecular basis for such associative learning. Specifically, the NMDA receptor is only activated when there is sufficient depolarization to unblock the receptor by freeing a magnesium ion from its channel. This enables the NMDA receptor to act as a coincidence detector, only opening when there is sustained activation of both the presynaptic and postsynaptic neurons. When opened, the NMDA receptor admits Glossary Blocking: a conditioning paradigm involving the pairing of a new conditioned stimulus (CS2) with an unconditioned stimulus (US) in the presence of an established conditioned cue (CS1). The prior conditioning of the CS1–US association ‘blocks’ or prevents conditioning of CS2 to the US. This occurs because the US is already fully predicted by CS1. However, in untreated patients with schizophrenia CS2 becomes conditioned as if the blocking phase never occurred. Glutamate hypofunction hypothesis of schizophrenia: this hypothesis emerged in light of the resemblance the symptoms of schizophrenia have to the effects of administering NMDA antagonists (e.g. phencyclidine) to healthy volunteers. The hypothesis proposes that glutamate dysfunction, and in particular NMDA receptor hypofunction, could act as a key pathogenic mechanism in schizophrenia. Latent inhibition: a conditioning paradigm in which subjects are inconsequentially pre-exposed to the to-be-conditioned stimulus. This slows the subsequent rate of conditioning when the stimulus is subsequently paired with an unconditioned stimulus. The behaviour of medication-naı¨ve patients remains un-modulated by this paradigm, suggesting an inability to ignore irrelevant stimuli. Prediction error: a concept drawn from machine learning; this is a key component of several reinforcement learning algorithms. In essence, it represents the discrepancy between an agent’s expectation of reward and the actual experienced outcome. This error term then drives a re-evaluation of the agent’s model of, or policy for, interaction with its environment. Psychosis: a neurobiologically founded abnormal state of mind, leading the individual to experience symptoms including hallucinations, delusions and thought disorder.
Corresponding author: Hall, J. ([email protected]). 0166-2236/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2009.01.011 Available online 6 May 2009
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In summary, CS–US associations are formed in classical conditioning by the modification of synaptic strengths. NMDA glutamate receptors provide a molecular mechanism for such associative synaptic plasticity. The formation of new associations results in changes in the firing of mesolimbic dopamine neurons, such that the CS itself comes to elicit dopaminergic firing (Figure 1). This alteration in dopamine firing acts as a predictive error signal and is responsible for mediating the learned motivational value of the CS.
Figure 1. Schematic display of phasic responses of meso-limbic dopamine neurons during learning. (a) Initially dopaminergic neurons fire in response to an unpredicted US. (b) A CS is introduced that is paired with the US forming a CS– US association via associative learning (as mediated through the NMDA receptor). Dopaminergic neuron firing is then seen in response to the predictive CS rather than the US. (c) If the expected US is subsequently omitted, a decrease in dopamine neuron firing is seen at the time of the expected US.
calcium ions, which alter second messenger signalling; this results in changes in gene expression and glutamate receptor availability, which mediates the change in synaptic strength. The importance of NMDA-receptor-mediated plasticity for associative learning has been demonstrated in several forms of classical conditioning, including Pavlovian aversive (fear) conditioning [7]. The acquisition of classically conditioned associations involves a change in phasic (short duration) dopaminergic activity [8,9] (Figure 1). Initially, neurons in the mesolimbic dopamine system increase phasic firing in response to the presentation of the US. As learning proceeds, these dopaminergic neurons transfer their phasic firing pattern such that they respond to the presentation of the predictive CS rather than the US. After learning, omission of the expected US leads to a decrease in the baseline rate of dopamine neuron firing (Figure 1). This dopamine signal is sufficient to sub-serve at least three processes [10,11]. The first is to modulate plasticity at glutamatergic synapses [11,12]. The second is to act as a predictive error signal, providing feedback as to whether or not the CS continues to be a reliable predictor of the expected US [8,13]. The third is to mediate the motivational impact, or incentive salience, of the CS [14,15]. These latter two functions are not necessarily separable and computationally represent the expected future value of a reward [10]. Dysregulation of the conditioned dopamine signal has been hypothesized to lead to psychotic symptoms by altering predictions about the rewarding value of stimuli, leading to the attribution of motivational importance to inappropriate stimuli [5,16– 18]. 360
Associative learning in schizophrenia Abnormalities of association formation have been considered to have a role in the pathogenesis of schizophrenia since Bleuler described ‘loosening of associations’ as one of the key features of the disorder [19]. Since then, considerable evidence of impairments in associative learning in schizophrenia has accumulated, and several theories relating these deficits to the symptoms of the disorder have been advanced [5,9,16,20–23]. Studies of classical conditioning are particularly informative, given that this type of implicit learning places no motivational demands on the subject, avoiding one of the confounds of schizophrenia research [24]. Here, we discuss evidence that both association formation and dopamine system activation are abnormal during classical conditioning in schizophrenia. Impairments of classical conditioning in schizophrenia have been demonstrated using a range of conditioning procedures measuring both autonomic and skeletomotor responses [24–30]. The most pronounced impairments are seen in tasks known to depend on associative learning mediated through the NMDA receptor, such as aversive (fear) conditioning. Aversive conditioning has been very well characterized in animal models and is known to require associative learning mediated by NMDA receptors in medial temporal lobe nuclei including the amygdala and hippocampus [7]. Patients with schizophrenia have consistently shown impairments in human aversive conditioning procedures [24,25,29,30]. Notably, this impairment is characterized not only by a decreased response to the CS but also by inappropriately increased responses to the unconditioned or control stimuli [29]. There is increasing evidence that the conditioned dopamine response is also abnormal in schizophrenia. Jensen and colleagues [29] have investigated the response of the ventral striatum, a target region of the meso-limbic dopamine system, during aversive classical conditioning in healthy subjects and individuals with schizophrenia. They found that in healthy participants this brain region is activated during conditioning in accordance with the predicted firing of the dopamine system, with ventral striatal responses being greater to the CS than to a control stimulus after learning [29]. However, in people with schizophrenia, this discrimination in striatal response was not seen [29]. In fact, the patients in this study were found to have increased activation of the ventral striatum to the control stimulus relative to healthy subjects. A similar loss of selective activation of the ventral striatum and midbrain to a conditioned cue has also been demonstrated in patients with psychosis during instrumental conditioning [31,32], and disrupted prediction error signals
Review have also been demonstrated in psychosis in prefrontal cortical regions [33]. Furthermore, patients with acute schizophrenia also show evidence of abnormal prediction error signalling in tests of latent inhibition and blocking [34,35]. In summary, there is evidence that patients with schizophrenia have impairments in basic associative learning processes, particularly those known to require plasticity mediated by the NMDA receptor [3]. These abnormalities of associative learning are manifested by abnormal behavioural and autonomic responses and abnormal regulation of the neural activity of dopamine-rich brain regions including the ventral striatum and midbrain ventral tegmental area. There is evidence that patients with schizophrenia fail to learn to ignore irrelevant stimuli and activate the limbic dopamine system inappropriately to neutral stimuli. Schizophrenia susceptibility genes and associative learning A major recent advance in psychiatric research has been the identification of plausible, well-replicated susceptibility genes for schizophrenia, based upon linkage, association and neurobiological evidence [1]. We suggest that these genes can be grouped into two main classes, which relate to the associative learning processes outlined earlier. The first group of genes has convergent effects on synaptic plasticity, in particular, those mediated through the NMDA glutamate receptor [1]. These genes include NRG1, Dysbindin, DAOA, GRM3 and DISC1 [1]. The second group of genes is involved in dopamine metabolism and signalling. These genes include COMT, DRD2 and PPP1R1B (encoding DARPP-32) [1,36,37]. Similar pathways have been implicated in studies of chromosomal abnormalities associated with schizophrenia [38,39]. In this section we look in further detail at NRG1 and COMT as exemplars of these two classes of schizophrenia susceptibility genes and examine how they modulate glutamate-dependent synaptic plasticity and dopamine metabolism, respectively. NRG1 was identified as a schizophrenia susceptibility gene in a large study in the Icelandic population, and association of the gene with risk for psychosis has now been confirmed in a range of populations [40,41]. ErbB4, a key central nervous system receptor for NRG1, has also been associated with schizophrenia [42–44]. NRG1 has a wide range of functions in the developing and adult central nervous system [45], but crucially it has been shown to play a key part in the modulation of synaptic plasticity at glutamatergic synapses. NRG1 is localized to synaptic regions [46] and the ErbB4 receptor is enriched in the postsynaptic density [47,48]. Both ErbB4 and NMDA receptors bind to PSD-95, a major scaffolding protein at excitatory synapses that can regulate synaptic function [47,48]. Furthermore, NRG1–ErbB4 signalling has been shown to alter the activity-dependent recruitment of both AMPA and NMDA receptors at glutamatergic synapses [49–51], resulting in the modulation of synaptic plasticity [49,50]. In human postmortem tissue, NRG1–ErbB4 signalling has been shown to suppress NMDA receptor activation, an effect that is enhanced in subjects with
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schizophrenia [52], providing a link between NRG1 and the ‘glutamate hypofunction’ hypothesis of schizophrenia [53]. NRG1, therefore, has a central role in the regulation of associative synaptic plasticity in the mammalian central nervous system (especially through effects mediated by the NMDA receptor), a function that is disrupted in schizophrenia. COMT is an enzyme involved in dopamine catabolism [54]. A common functional polymorphism exists in the human COMT gene that comprises a methionine (Met) to valine (Val) substitution at the 158/108 locus [55]. The evolutionarily more recent Met allele has fourfold lower enzymatic activity, which results in increased dopamine availability [55]. The COMT gene lies in a region of chromosome 22q associated with risk for schizophrenia [39,54]. Several studies have investigated the relationship of the COMT Val158Met polymorphism with risk for the disorder [54]. Case-control studies have failed to show a clear association of COMT genotypes with schizophrenia, although there is some evidence that the Val allele is associated with a small increase in risk [54,56–58]. More convincing evidence for an association of the COMT Val allele with schizophrenia is provided by family-based studies that suggest that the Val allele might exert a modulatory influence on the development of psychosis in the context of an existing genetic risk [58–60]. The association of the COMT Val allele with schizophrenia at first seems to be paradoxical because the Val allele is associated with increased dopamine catabolism, whereas schizophrenia is very likely to be a disorder characterized by an elevation of subcortical dopamine [61]. However, postmortem and positron emission tomography studies indicate that the COMT Val allele is associated with elevated subcortical dopamine synthesis [62,63]. In addition, COMT is selectively involved in regulating tonic, rather than phasic, dopamine levels in subcortical areas [4], with the high-activity COMT Val allele being associated with lower tonic dopamine levels. Decreased tonic dopamine might act to increase phasic dopamine release by reducing the activation of inhibitory presynaptic dopamine autoreceptors [4]. The COMT Val allele could, therefore, contribute to the development of psychosis in vulnerable populations by potentiating phasic subcortical dopamine responses to conditioned stimuli. In summary, NRG1 and COMT are exemplars of two classes of genes associated with schizophrenia. The first class, which includes NRG1, has direct effects on synaptic plasticity and association formation, particularly through actions at glutamatergic synapses. The second class, including COMT, impacts on meso-limbic dopamine signalling, affecting both learning and the attribution of motivational importance to conditioned stimuli. We suggest that these classes of genes interact to increase the risk of psychosis in manner similar to that previously discussed in relation to the disconnection hypothesis of schizophrenia [3,23]. Interactions between classes of schizophrenia susceptibility genes The formation of CS–US associations is dependent on NMDA-receptor-mediated plasticity in brain regions such 361
Review as the prefrontal cortex and extended amygdala, which regulate the phasic firing of meso-limbic dopamine neurons [64]. Genetic variation impacting on NMDA-receptormediated plasticity in these brain areas might alter the fidelity of CS–US association formation, causing a dysregulation of control of the meso-limbic dopamine firing and potentially producing a state of vulnerability for psychosis. The effects of such altered association formation could be greatly magnified by further genetic (or environmental) factors impacting on the dopamine system to increase the ‘gain’ of the dysregulated phasic dopamine signal, resulting in progression to a frank psychotic state. Notably, such altered dopamine signalling would also lead to further impairments in NMDA-mediated association formation, given that dopamine has modulatory effects on plasticity at glutamatergic synapses [11,12,65–67]. Genes affecting NMDA-receptor-mediated plasticity and dopamine signalling might, therefore, interact to produce alterations in both the regulation and amplitude of the meso-limbic dopamine signal, resulting in inappropriate stimuli gaining motivational importance. Genetic factors affecting the integration of glutamatergic and dopaminergic signals would particularly be expected to increase psychosis risk, as is the case for PPP1R1B [37,68]. In the next section we examine how genes of these two classes might lead to the development of psychosis, by drawing on results from the EHRS and focusing on NRG1 and COMT as exemplars. Genetic effects in the EHRS The EHRS was a 10-year cohort study of young people at risk of schizophrenia for genetic (familial) reasons [69]. Subjects with at least two close relatives with schizophrenia were recruited between the ages of 16 and 25 years and followed up to determine whether or not they developed the disorder. All participants had regular detailed clinical interviews, brain imaging, neuropsychological testing and, latterly, genetic testing. One hundred and fifty seven suitable individuals were recruited into the study and follow-up data was available for a large proportion of these high-risk subjects. Twenty one subjects (13%) went on to develop schizophrenia but, notably, a further 40% of this genetically enriched sample developed transient or isolated psychotic symptoms (delusions or hallucinations) that were not in themselves disabling or sufficient for the diagnosis of schizophrenia [69] (Figure 2). The development of such isolated and transient psychotic symptoms might represent a heritable vulnerability state for schizophrenia, which only manifests as syndromal illness in a minority of individuals. We investigated the impact of risk-associated genetic variation in NRG1 on the development of psychosis in the EHRS [70]. Subjects were genotyped variants in NRG1 previously identified as a conferring risk for schizophrenia in a range of populations [40,41]. We found that a specific polymorphism, SNP8NRG243177 (rs6694992), was associated with a highly significant increase in the risk of developing psychotic symptoms [70]. Notably, this association was with the broader phenotype of psychotic symptoms, rather than with the development of syndromal schizophrenia [70], paralleling a previous study showing an 362
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Figure 2. A model of the development of psychotic symptoms and schizophrenia based on results from the EHRS. Out of a population of subjects at high genetic risk of schizophrenia a large proportion (>40%) develop psychotic symptoms with associated alterations in brain structure and activation [80] (a). However, in the majority of subjects these symptoms remain isolated and transient and do not result in the disabling syndrome of schizophrenia. A smaller proportion (13%) of the total at-risk population goes on to develop syndromal schizophrenia (b). These subjects show further changes in cerebral structure and function [80]. In the EHRS, increased risk for developing psychotic symptoms (a) was associated with genetic variation in the NRG1 gene, whereas increased risk for development of syndromal schizophrenia (b) was associated with genetic variation in COMT.
association of NRG1 with schizotypal features [71]. The association with SNP8NRG243177 was of particular interest because this polymorphism has been shown to act as a functional promoter variant, affecting the expression of Type IV NRG1, with the risk allele (T) increasing levels of type IV NRG1 expression [72,73]. Because NRG1 has been shown to inhibit NMDA receptor activation in the prefrontal cortex [51,52], increased expression of NRG1 type IV might contribute to glutamate hypofunction in schizophrenia. Indeed, we found that in the EHRS possession of the risk genotype (TT) was associated with decreased activation of the prefrontal cortex in functional magnetic resonance imaging [70] (Figure 3).
Figure 3. Effect of the variation in NRG1 on prefrontal cortex activation in subjects at high genetic risk of schizophrenia. Risk-associated genetic variation at NRG1 SNP8NRG243177 was associated with decreased prefrontal cortex activation in the EHRS (a), with parameter estimates revealing a dose-dependent effect of the riskassociated T allele on medial prefrontal activity (b) [70].
Review We have also studied the effects of the COMT Val158Met polymorphism in the EHRS [59]. Here, we found a different pattern of association from NRG1. The COMT genotype was associated with the development of frank psychosis and syndromal schizophrenia. There was a dosedependent effect of the Val allele in this familial sample, such that individuals with the Val/Val genotype had the highest risk of developing schizophrenia. In addition, Val/ Val carriers showed inefficient prefrontal cortex activation and increased activation of the ventral striatum during functional magnetic resonance imaging (A.M.M., unpublished). In summary, the results of the EHRS suggest that there is a heritable risk state for schizophrenia characterized by the presence of transient or isolated psychotic symptoms. Only a subset of these individuals goes on to develop syndromal schizophrenia, in which these psychotic symptoms gain an importance and dominance that comes to govern the subject’s behaviour, causing disability. Genetic variation in NRG1, a gene known to affect NMDA receptor function, was associated in the sample with the development of the risk state. In addition, genetic variation in COMT, associated with increased subcortical dopamine responses, was associated with transition to the full syndrome of schizophrenia with the development of a sustained and disabling psychotic state. Conclusions We suggest that schizophrenia susceptibility genes can be considered to fall into two broad classes: those directly impacting on synaptic plasticity, especially mediated through the NMDA receptor, and those affecting dopamine metabolism and signalling. We argue that these genes have an interactive effect on risk for psychosis and that this interaction can be understood in the context of associative learning. Genetic variation affecting synaptic plasticity can lead to abnormalities in information encoding that result in a state of heightened vulnerability for psychosis characterized by sub-syndromal symptoms. However, these symptoms only develop into a full psychotic syndrome if there is associated dysregulation of mesostriatal dopamine transmission causing the abnormal experiences to gain motivational importance, dominating the behaviour of the sufferer. This perturbation of the dopamine system can result from genetic factors (such as COMT genotype) but might also be caused by environmental factors (such as illicit drugs and psychosocial ‘stress’), representing a point of convergence for multiple risk factors for psychosis [74]. It follows that genes or environmental factors impacting on both glutamatergic and dopaminergic mechanisms might have a particularly high potential for the induction of psychotic symptoms [16,37,75]. There are several key outstanding questions and issues to be addressed. First, as large-scale efforts are undertaken to identify further susceptibility genes for schizophrenia it remains to be determined whether future risk factors will also show convergence on glutamatergic and dopaminergic pathways. Second, although initial evidence supports genetic epistasis between COMT and other schizophrenia susceptibility genes [76], there is a need for large-scale
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studies investigating epistasis between classes of susceptibility genes. Third, further investigation is required into how genetic variation susceptibility genes impact on plasticity and dopamine regulation, and how this relates to tonic and phasic dopamine release [4,9,64]. Fourthly, few studies have, thus far, directly investigated the impact of schizophrenia susceptibility genes on associative learning in either animal or human models [77,78]. Finally, it remains to be determined how altered associative learning and dopamine dysregulation map on to the different symptom domains of the schizophrenia syndrome with studies showing a range of symptom associations [18,29,31–33,79]. Disclosure statement J.H., A.M.M. and S.M.L. have received research funding from the Translational Medicine Research Collaboration (www.tmrc.co.uk), which is, in part, funded by Wyeth Pharmaceuticals (www.wyeth.co.uk). Acknowledgements J.H. is supported by a Medical Research Council (MRC) Clinical Research Training Fellowship (www.mrc.ac.uk). The EHRS was funded by the MRC and additional funding was provided by the Dr Mortimer and Theresa Sackler Foundation. We thank Rudolf Cardinal, John Parkinson, Simon Killcross and Liat Levita for helpful comments on drafts of the manuscript.
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Review 73 Tan, W. et al. (2007) Molecular cloning of a brain-specific, developmentally regulated neuregulin 1 (NRG1) isoform and identification of a functional promoter variant associated with schizophrenia. J. Biol. Chem. 282, 24343–24351 74 Broome, M.R. et al. (2005) What causes the onset of psychosis? Schizophr. Res. 79, 23–34 75 Roy, K. et al. (2007) Loss of erbB signaling in oligodendrocytes alters myelin and dopaminergic function, a potential mechanism for neuropsychiatric disorders. Proc. Natl. Acad. Sci. U. S. A. 104, 8131–8136 76 Nicodemus, K.K. et al. (2007) Evidence for statistical epistasis between catechol-O-methyltransferase (COMT) and polymorphisms in RGS4, G72 (DAOA), GRM3, and DISC1: influence on risk of schizophrenia. Hum. Genet. 120, 889–906
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77 Frank, M.J. et al. (2007) Genetic triple dissociation reveals multiple roles for dopamine in reinforcement learning. Proc. Natl. Acad. Sci. U. S. A. 104, 16311–16316 78 Heyser, C.J. et al. (2000) DARPP-32 knockout mice exhibit impaired reversal learning in a discriminated operant task. Brain Res. 867, 122– 130 79 Moran, P.M. et al. (2008) Abnormal prediction error is associated with negative and depressive symptoms in schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 32, 116–123 80 Lawrie, S.M. et al. (2008) Brain structure and function changes during the development of schizophrenia: the evidence from studies of subjects at increased genetic risk. Schizophr. Bull. 34, 330–340
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Associative learning and the genetics of schizophrenia Jeremy Hall1, Liana Romaniuk1, Andrew M. McIntosh1, J. Douglas Steele2, Eve C. Johnstone1 and Stephen M. Lawrie1 1 2
Division of Psychiatry, University of Edinburgh, Edinburgh, EH10 5HF, UK Section of Psychiatry and Behavioural Sciences, University of Dundee, Dundee, DD1 9SY, UK
Several well-validated susceptibility genes for schizophrenia have now been identified. We suggest that these genes can be divided into two broad classes. Those in the first class have direct effects on synaptic plasticity mediated through actions at glutamatergic synapses; those in the second class impact on meso-limbic dopamine signalling. We argue that these genes have an interactive effect on risk for psychosis and that this interaction can be understood in the context of associative learning theory. We illustrate how genetic variation in genes from these classes can contribute to the development of psychosis using data from the Edinburgh High Risk Study of schizophrenia. Introduction Recent advances in genetics have led to the identification of several well-supported susceptibility genes for schizophrenia [1,2]. These genes have an apparently disparate range of functions, raising questions about the mechanisms through which they contribute to the development of psychosis (see Glossary). Previous authors have noted a convergence on glutamatergic and dopaminergic pathways [1– 3]. This has led to the suggestion that genes associated with schizophrenia might have a common impact on molecular processes involved in associative learning [3,4]. If this is the case, associative learning theory can provide a framework for understanding how genetic variation in susceptibility genes causes increased risk for psychosis [3–5]. In this article we first outline some key processes in associative learning before reviewing the evidence that such processes are abnormal in schizophrenia. We discuss the evidence that schizophrenia susceptibility genes impact on molecular processes involved in associative learning, focusing on neuregulin-1 (NRG1) and catecholO-methyl transferase (COMT) as examples. Finally, we examine how functional genetic variation can contribute to the development of psychosis using data from our own work in the Edinburgh High Risk Study of schizophrenia (EHRS). Overall, we aim to link the functions of schizophrenia susceptibility genes to potential mechanisms underlying the development of psychotic symptoms. Key concepts in associative learning Associative learning has been extensively studied using classical (Pavlovian) and instrumental conditioning tasks.
A full discussion of associative learning theory is beyond the scope of this review [6]. Instead, we consider some fundamental features of associative learning that are of relevance to the actions of schizophrenia susceptibility genes, focusing on classical conditioning. Classical conditioning is the process by which an initially neutral stimulus (the conditioned stimulus [CS]), by virtue of presentation with a biologically important event (the unconditioned stimulus [US]), comes itself to elicit a characteristic response (the conditioned response [CR]). This CR often resembles the response produced by the presentation of the US alone, known as the unconditioned response (UR). This form of learning can be understood in terms of associative synaptic plasticity, demonstrated electrophysiologically as long-term potentiation (LTP). The properties of the N-methyl-D-aspartic acid (NMDA) glutamate receptor provide a molecular basis for such associative learning. Specifically, the NMDA receptor is only activated when there is sufficient depolarization to unblock the receptor by freeing a magnesium ion from its channel. This enables the NMDA receptor to act as a coincidence detector, only opening when there is sustained activation of both the presynaptic and postsynaptic neurons. When opened, the NMDA receptor admits Glossary Blocking: a conditioning paradigm involving the pairing of a new conditioned stimulus (CS2) with an unconditioned stimulus (US) in the presence of an established conditioned cue (CS1). The prior conditioning of the CS1–US association ‘blocks’ or prevents conditioning of CS2 to the US. This occurs because the US is already fully predicted by CS1. However, in untreated patients with schizophrenia CS2 becomes conditioned as if the blocking phase never occurred. Glutamate hypofunction hypothesis of schizophrenia: this hypothesis emerged in light of the resemblance the symptoms of schizophrenia have to the effects of administering NMDA antagonists (e.g. phencyclidine) to healthy volunteers. The hypothesis proposes that glutamate dysfunction, and in particular NMDA receptor hypofunction, could act as a key pathogenic mechanism in schizophrenia. Latent inhibition: a conditioning paradigm in which subjects are inconsequentially pre-exposed to the to-be-conditioned stimulus. This slows the subsequent rate of conditioning when the stimulus is subsequently paired with an unconditioned stimulus. The behaviour of medication-naı¨ve patients remains un-modulated by this paradigm, suggesting an inability to ignore irrelevant stimuli. Prediction error: a concept drawn from machine learning; this is a key component of several reinforcement learning algorithms. In essence, it represents the discrepancy between an agent’s expectation of reward and the actual experienced outcome. This error term then drives a re-evaluation of the agent’s model of, or policy for, interaction with its environment. Psychosis: a neurobiologically founded abnormal state of mind, leading the individual to experience symptoms including hallucinations, delusions and thought disorder.
Corresponding author: Hall, J. ([email protected]). 0166-2236/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2009.01.011 Available online 6 May 2009
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In summary, CS–US associations are formed in classical conditioning by the modification of synaptic strengths. NMDA glutamate receptors provide a molecular mechanism for such associative synaptic plasticity. The formation of new associations results in changes in the firing of mesolimbic dopamine neurons, such that the CS itself comes to elicit dopaminergic firing (Figure 1). This alteration in dopamine firing acts as a predictive error signal and is responsible for mediating the learned motivational value of the CS.
Figure 1. Schematic display of phasic responses of meso-limbic dopamine neurons during learning. (a) Initially dopaminergic neurons fire in response to an unpredicted US. (b) A CS is introduced that is paired with the US forming a CS– US association via associative learning (as mediated through the NMDA receptor). Dopaminergic neuron firing is then seen in response to the predictive CS rather than the US. (c) If the expected US is subsequently omitted, a decrease in dopamine neuron firing is seen at the time of the expected US.
calcium ions, which alter second messenger signalling; this results in changes in gene expression and glutamate receptor availability, which mediates the change in synaptic strength. The importance of NMDA-receptor-mediated plasticity for associative learning has been demonstrated in several forms of classical conditioning, including Pavlovian aversive (fear) conditioning [7]. The acquisition of classically conditioned associations involves a change in phasic (short duration) dopaminergic activity [8,9] (Figure 1). Initially, neurons in the mesolimbic dopamine system increase phasic firing in response to the presentation of the US. As learning proceeds, these dopaminergic neurons transfer their phasic firing pattern such that they respond to the presentation of the predictive CS rather than the US. After learning, omission of the expected US leads to a decrease in the baseline rate of dopamine neuron firing (Figure 1). This dopamine signal is sufficient to sub-serve at least three processes [10,11]. The first is to modulate plasticity at glutamatergic synapses [11,12]. The second is to act as a predictive error signal, providing feedback as to whether or not the CS continues to be a reliable predictor of the expected US [8,13]. The third is to mediate the motivational impact, or incentive salience, of the CS [14,15]. These latter two functions are not necessarily separable and computationally represent the expected future value of a reward [10]. Dysregulation of the conditioned dopamine signal has been hypothesized to lead to psychotic symptoms by altering predictions about the rewarding value of stimuli, leading to the attribution of motivational importance to inappropriate stimuli [5,16– 18]. 360
Associative learning in schizophrenia Abnormalities of association formation have been considered to have a role in the pathogenesis of schizophrenia since Bleuler described ‘loosening of associations’ as one of the key features of the disorder [19]. Since then, considerable evidence of impairments in associative learning in schizophrenia has accumulated, and several theories relating these deficits to the symptoms of the disorder have been advanced [5,9,16,20–23]. Studies of classical conditioning are particularly informative, given that this type of implicit learning places no motivational demands on the subject, avoiding one of the confounds of schizophrenia research [24]. Here, we discuss evidence that both association formation and dopamine system activation are abnormal during classical conditioning in schizophrenia. Impairments of classical conditioning in schizophrenia have been demonstrated using a range of conditioning procedures measuring both autonomic and skeletomotor responses [24–30]. The most pronounced impairments are seen in tasks known to depend on associative learning mediated through the NMDA receptor, such as aversive (fear) conditioning. Aversive conditioning has been very well characterized in animal models and is known to require associative learning mediated by NMDA receptors in medial temporal lobe nuclei including the amygdala and hippocampus [7]. Patients with schizophrenia have consistently shown impairments in human aversive conditioning procedures [24,25,29,30]. Notably, this impairment is characterized not only by a decreased response to the CS but also by inappropriately increased responses to the unconditioned or control stimuli [29]. There is increasing evidence that the conditioned dopamine response is also abnormal in schizophrenia. Jensen and colleagues [29] have investigated the response of the ventral striatum, a target region of the meso-limbic dopamine system, during aversive classical conditioning in healthy subjects and individuals with schizophrenia. They found that in healthy participants this brain region is activated during conditioning in accordance with the predicted firing of the dopamine system, with ventral striatal responses being greater to the CS than to a control stimulus after learning [29]. However, in people with schizophrenia, this discrimination in striatal response was not seen [29]. In fact, the patients in this study were found to have increased activation of the ventral striatum to the control stimulus relative to healthy subjects. A similar loss of selective activation of the ventral striatum and midbrain to a conditioned cue has also been demonstrated in patients with psychosis during instrumental conditioning [31,32], and disrupted prediction error signals
Review have also been demonstrated in psychosis in prefrontal cortical regions [33]. Furthermore, patients with acute schizophrenia also show evidence of abnormal prediction error signalling in tests of latent inhibition and blocking [34,35]. In summary, there is evidence that patients with schizophrenia have impairments in basic associative learning processes, particularly those known to require plasticity mediated by the NMDA receptor [3]. These abnormalities of associative learning are manifested by abnormal behavioural and autonomic responses and abnormal regulation of the neural activity of dopamine-rich brain regions including the ventral striatum and midbrain ventral tegmental area. There is evidence that patients with schizophrenia fail to learn to ignore irrelevant stimuli and activate the limbic dopamine system inappropriately to neutral stimuli. Schizophrenia susceptibility genes and associative learning A major recent advance in psychiatric research has been the identification of plausible, well-replicated susceptibility genes for schizophrenia, based upon linkage, association and neurobiological evidence [1]. We suggest that these genes can be grouped into two main classes, which relate to the associative learning processes outlined earlier. The first group of genes has convergent effects on synaptic plasticity, in particular, those mediated through the NMDA glutamate receptor [1]. These genes include NRG1, Dysbindin, DAOA, GRM3 and DISC1 [1]. The second group of genes is involved in dopamine metabolism and signalling. These genes include COMT, DRD2 and PPP1R1B (encoding DARPP-32) [1,36,37]. Similar pathways have been implicated in studies of chromosomal abnormalities associated with schizophrenia [38,39]. In this section we look in further detail at NRG1 and COMT as exemplars of these two classes of schizophrenia susceptibility genes and examine how they modulate glutamate-dependent synaptic plasticity and dopamine metabolism, respectively. NRG1 was identified as a schizophrenia susceptibility gene in a large study in the Icelandic population, and association of the gene with risk for psychosis has now been confirmed in a range of populations [40,41]. ErbB4, a key central nervous system receptor for NRG1, has also been associated with schizophrenia [42–44]. NRG1 has a wide range of functions in the developing and adult central nervous system [45], but crucially it has been shown to play a key part in the modulation of synaptic plasticity at glutamatergic synapses. NRG1 is localized to synaptic regions [46] and the ErbB4 receptor is enriched in the postsynaptic density [47,48]. Both ErbB4 and NMDA receptors bind to PSD-95, a major scaffolding protein at excitatory synapses that can regulate synaptic function [47,48]. Furthermore, NRG1–ErbB4 signalling has been shown to alter the activity-dependent recruitment of both AMPA and NMDA receptors at glutamatergic synapses [49–51], resulting in the modulation of synaptic plasticity [49,50]. In human postmortem tissue, NRG1–ErbB4 signalling has been shown to suppress NMDA receptor activation, an effect that is enhanced in subjects with
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schizophrenia [52], providing a link between NRG1 and the ‘glutamate hypofunction’ hypothesis of schizophrenia [53]. NRG1, therefore, has a central role in the regulation of associative synaptic plasticity in the mammalian central nervous system (especially through effects mediated by the NMDA receptor), a function that is disrupted in schizophrenia. COMT is an enzyme involved in dopamine catabolism [54]. A common functional polymorphism exists in the human COMT gene that comprises a methionine (Met) to valine (Val) substitution at the 158/108 locus [55]. The evolutionarily more recent Met allele has fourfold lower enzymatic activity, which results in increased dopamine availability [55]. The COMT gene lies in a region of chromosome 22q associated with risk for schizophrenia [39,54]. Several studies have investigated the relationship of the COMT Val158Met polymorphism with risk for the disorder [54]. Case-control studies have failed to show a clear association of COMT genotypes with schizophrenia, although there is some evidence that the Val allele is associated with a small increase in risk [54,56–58]. More convincing evidence for an association of the COMT Val allele with schizophrenia is provided by family-based studies that suggest that the Val allele might exert a modulatory influence on the development of psychosis in the context of an existing genetic risk [58–60]. The association of the COMT Val allele with schizophrenia at first seems to be paradoxical because the Val allele is associated with increased dopamine catabolism, whereas schizophrenia is very likely to be a disorder characterized by an elevation of subcortical dopamine [61]. However, postmortem and positron emission tomography studies indicate that the COMT Val allele is associated with elevated subcortical dopamine synthesis [62,63]. In addition, COMT is selectively involved in regulating tonic, rather than phasic, dopamine levels in subcortical areas [4], with the high-activity COMT Val allele being associated with lower tonic dopamine levels. Decreased tonic dopamine might act to increase phasic dopamine release by reducing the activation of inhibitory presynaptic dopamine autoreceptors [4]. The COMT Val allele could, therefore, contribute to the development of psychosis in vulnerable populations by potentiating phasic subcortical dopamine responses to conditioned stimuli. In summary, NRG1 and COMT are exemplars of two classes of genes associated with schizophrenia. The first class, which includes NRG1, has direct effects on synaptic plasticity and association formation, particularly through actions at glutamatergic synapses. The second class, including COMT, impacts on meso-limbic dopamine signalling, affecting both learning and the attribution of motivational importance to conditioned stimuli. We suggest that these classes of genes interact to increase the risk of psychosis in manner similar to that previously discussed in relation to the disconnection hypothesis of schizophrenia [3,23]. Interactions between classes of schizophrenia susceptibility genes The formation of CS–US associations is dependent on NMDA-receptor-mediated plasticity in brain regions such 361
Review as the prefrontal cortex and extended amygdala, which regulate the phasic firing of meso-limbic dopamine neurons [64]. Genetic variation impacting on NMDA-receptormediated plasticity in these brain areas might alter the fidelity of CS–US association formation, causing a dysregulation of control of the meso-limbic dopamine firing and potentially producing a state of vulnerability for psychosis. The effects of such altered association formation could be greatly magnified by further genetic (or environmental) factors impacting on the dopamine system to increase the ‘gain’ of the dysregulated phasic dopamine signal, resulting in progression to a frank psychotic state. Notably, such altered dopamine signalling would also lead to further impairments in NMDA-mediated association formation, given that dopamine has modulatory effects on plasticity at glutamatergic synapses [11,12,65–67]. Genes affecting NMDA-receptor-mediated plasticity and dopamine signalling might, therefore, interact to produce alterations in both the regulation and amplitude of the meso-limbic dopamine signal, resulting in inappropriate stimuli gaining motivational importance. Genetic factors affecting the integration of glutamatergic and dopaminergic signals would particularly be expected to increase psychosis risk, as is the case for PPP1R1B [37,68]. In the next section we examine how genes of these two classes might lead to the development of psychosis, by drawing on results from the EHRS and focusing on NRG1 and COMT as exemplars. Genetic effects in the EHRS The EHRS was a 10-year cohort study of young people at risk of schizophrenia for genetic (familial) reasons [69]. Subjects with at least two close relatives with schizophrenia were recruited between the ages of 16 and 25 years and followed up to determine whether or not they developed the disorder. All participants had regular detailed clinical interviews, brain imaging, neuropsychological testing and, latterly, genetic testing. One hundred and fifty seven suitable individuals were recruited into the study and follow-up data was available for a large proportion of these high-risk subjects. Twenty one subjects (13%) went on to develop schizophrenia but, notably, a further 40% of this genetically enriched sample developed transient or isolated psychotic symptoms (delusions or hallucinations) that were not in themselves disabling or sufficient for the diagnosis of schizophrenia [69] (Figure 2). The development of such isolated and transient psychotic symptoms might represent a heritable vulnerability state for schizophrenia, which only manifests as syndromal illness in a minority of individuals. We investigated the impact of risk-associated genetic variation in NRG1 on the development of psychosis in the EHRS [70]. Subjects were genotyped variants in NRG1 previously identified as a conferring risk for schizophrenia in a range of populations [40,41]. We found that a specific polymorphism, SNP8NRG243177 (rs6694992), was associated with a highly significant increase in the risk of developing psychotic symptoms [70]. Notably, this association was with the broader phenotype of psychotic symptoms, rather than with the development of syndromal schizophrenia [70], paralleling a previous study showing an 362
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Figure 2. A model of the development of psychotic symptoms and schizophrenia based on results from the EHRS. Out of a population of subjects at high genetic risk of schizophrenia a large proportion (>40%) develop psychotic symptoms with associated alterations in brain structure and activation [80] (a). However, in the majority of subjects these symptoms remain isolated and transient and do not result in the disabling syndrome of schizophrenia. A smaller proportion (13%) of the total at-risk population goes on to develop syndromal schizophrenia (b). These subjects show further changes in cerebral structure and function [80]. In the EHRS, increased risk for developing psychotic symptoms (a) was associated with genetic variation in the NRG1 gene, whereas increased risk for development of syndromal schizophrenia (b) was associated with genetic variation in COMT.
association of NRG1 with schizotypal features [71]. The association with SNP8NRG243177 was of particular interest because this polymorphism has been shown to act as a functional promoter variant, affecting the expression of Type IV NRG1, with the risk allele (T) increasing levels of type IV NRG1 expression [72,73]. Because NRG1 has been shown to inhibit NMDA receptor activation in the prefrontal cortex [51,52], increased expression of NRG1 type IV might contribute to glutamate hypofunction in schizophrenia. Indeed, we found that in the EHRS possession of the risk genotype (TT) was associated with decreased activation of the prefrontal cortex in functional magnetic resonance imaging [70] (Figure 3).
Figure 3. Effect of the variation in NRG1 on prefrontal cortex activation in subjects at high genetic risk of schizophrenia. Risk-associated genetic variation at NRG1 SNP8NRG243177 was associated with decreased prefrontal cortex activation in the EHRS (a), with parameter estimates revealing a dose-dependent effect of the riskassociated T allele on medial prefrontal activity (b) [70].
Review We have also studied the effects of the COMT Val158Met polymorphism in the EHRS [59]. Here, we found a different pattern of association from NRG1. The COMT genotype was associated with the development of frank psychosis and syndromal schizophrenia. There was a dosedependent effect of the Val allele in this familial sample, such that individuals with the Val/Val genotype had the highest risk of developing schizophrenia. In addition, Val/ Val carriers showed inefficient prefrontal cortex activation and increased activation of the ventral striatum during functional magnetic resonance imaging (A.M.M., unpublished). In summary, the results of the EHRS suggest that there is a heritable risk state for schizophrenia characterized by the presence of transient or isolated psychotic symptoms. Only a subset of these individuals goes on to develop syndromal schizophrenia, in which these psychotic symptoms gain an importance and dominance that comes to govern the subject’s behaviour, causing disability. Genetic variation in NRG1, a gene known to affect NMDA receptor function, was associated in the sample with the development of the risk state. In addition, genetic variation in COMT, associated with increased subcortical dopamine responses, was associated with transition to the full syndrome of schizophrenia with the development of a sustained and disabling psychotic state. Conclusions We suggest that schizophrenia susceptibility genes can be considered to fall into two broad classes: those directly impacting on synaptic plasticity, especially mediated through the NMDA receptor, and those affecting dopamine metabolism and signalling. We argue that these genes have an interactive effect on risk for psychosis and that this interaction can be understood in the context of associative learning. Genetic variation affecting synaptic plasticity can lead to abnormalities in information encoding that result in a state of heightened vulnerability for psychosis characterized by sub-syndromal symptoms. However, these symptoms only develop into a full psychotic syndrome if there is associated dysregulation of mesostriatal dopamine transmission causing the abnormal experiences to gain motivational importance, dominating the behaviour of the sufferer. This perturbation of the dopamine system can result from genetic factors (such as COMT genotype) but might also be caused by environmental factors (such as illicit drugs and psychosocial ‘stress’), representing a point of convergence for multiple risk factors for psychosis [74]. It follows that genes or environmental factors impacting on both glutamatergic and dopaminergic mechanisms might have a particularly high potential for the induction of psychotic symptoms [16,37,75]. There are several key outstanding questions and issues to be addressed. First, as large-scale efforts are undertaken to identify further susceptibility genes for schizophrenia it remains to be determined whether future risk factors will also show convergence on glutamatergic and dopaminergic pathways. Second, although initial evidence supports genetic epistasis between COMT and other schizophrenia susceptibility genes [76], there is a need for large-scale
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studies investigating epistasis between classes of susceptibility genes. Third, further investigation is required into how genetic variation susceptibility genes impact on plasticity and dopamine regulation, and how this relates to tonic and phasic dopamine release [4,9,64]. Fourthly, few studies have, thus far, directly investigated the impact of schizophrenia susceptibility genes on associative learning in either animal or human models [77,78]. Finally, it remains to be determined how altered associative learning and dopamine dysregulation map on to the different symptom domains of the schizophrenia syndrome with studies showing a range of symptom associations [18,29,31–33,79]. Disclosure statement J.H., A.M.M. and S.M.L. have received research funding from the Translational Medicine Research Collaboration (www.tmrc.co.uk), which is, in part, funded by Wyeth Pharmaceuticals (www.wyeth.co.uk). Acknowledgements J.H. is supported by a Medical Research Council (MRC) Clinical Research Training Fellowship (www.mrc.ac.uk). The EHRS was funded by the MRC and additional funding was provided by the Dr Mortimer and Theresa Sackler Foundation. We thank Rudolf Cardinal, John Parkinson, Simon Killcross and Liat Levita for helpful comments on drafts of the manuscript.
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