Neuron Perspective

APossibleRolefortheStriatum in the Pathogenesis of the Cognitive Symptoms of Schizophrenia

Eleanor H. Simpson,2,4,* Christoph Kellendonk,2,3,4 and Eric Kandel1,2,4,5,6 1Department of Neuroscience 2Department of Psychiatry 3Department of Pharmacology 4The Lieber Center for Schizophrenia Research 5The Kavli Institute for Brain Science 6Howard Hughes Medical Institute Columbia University and New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY 10032, USA *Correspondence: [email protected] DOI 10.1016/j.neuron.2010.02.014

The cognitive symptoms of schizophrenia are largely resistant to current treatment and are thus a life-long burden of the illness. Studies of cognitive symptoms have commonly focused on prefrontal cortex because of its demonstrated importance for executive function and working memory—key components of the deficit. The role of striatal-cortical circuitry and therefore the striatum itself has received much less attention. Here we review longstanding evidence that the striatum and its cortical connections are critical for complex cognition and discuss emerging evidence of the striatum’s potential involvement in cognitive symptoms. Finally, we suggest how mouse models might test ideas about the contribution of early striatal dysfunction to the cogni- tive symptoms of schizophrenia.

The cognitive symptoms of schizophrenia present early in the and cognitive symptoms are not, and therefore, as a result, these disease, and unlike positive symptoms, including hallucinations two symptom clusters, and especially the cognitive symptoms and delusions, cognitive symptoms are largely resistant to that are so debilitating, have become a major focus in schizo- current treatment and therefore persist throughout life. Many phrenia research (Keefe et al., 2007). The cognitive symptoms studies of cognitive symptoms have focused on the prefrontal of schizophrenia include deficits in semantic and explicit cortex because of its demonstrated importance for executive memory, as well as deficits in attention, working memory, and function and working memory—key components of the cognitive executive function (Cirillo and Seidman, 2003; Goldman-Rakic, deficit. However, the role of striatal cortical circuitry and there- 1994). The cognitive deficits are not unique to schizophrenia. fore the striatum itself has received much less attention than But because they affect mental abilities needed for day-to-day other brain structures affected in schizophrenia, such as the functioning as well as planning for the future, the severity of these prefrontal cortex and temporal lobe. Here we review longstand- symptoms are highly predictive of a patient’s long-term prog- ing evidence that supports the idea that the striatum, and its nosis, more predictive than the positive symptoms (Green, 1996). cortical connections, are critical for complex cognitive functions, The relevance of the cognitive symptoms of schizophrenia and we discuss the emerging evidence of the striatum’s potential was already understood more than a century ago by Kraepelin, involvement in generating cognitive symptoms of schizophrenia. who in 1893 divided the major psychotic illnesses into two Finally, we provide a general outline of how mouse models might groups by differentiating patients with ‘‘dementia praecox,’’ or test ideas about early striatal dysfunction’s contribution to the premature dementia (later termed schizophrenia by Eugene cognitive symptoms of schizophrenia. Bleuler), from manic depressive illness based on their disordered thought. Kraeplin was also the first to recognize that patients The Importance of Understanding the Cognitive with dementia praecox share many of the behavioral abnormal- Symptoms of Schizophrenia ities observed in the dementia of patients with lesions of the Schizophrenia is formally characterized by three distinct frontal lobes (Kraepelin, 1919). Patients with frontal lobe damage symptom clusters: positive, negative, and cognitive. The positive and patients with schizophrenia suffer from defects in executive symptoms refer to hallucinations and delusions, psychotic function that are measured on tasks such as the Wisconsin Card abnormalities in perception and reality testing. The negative Sorting Test (WCST), the Stroop Task, the "Tower of London" symptoms refer to social withdrawal, lack of motivation, and task, and the N-back test (Kolb and Whishaw, 1983)(Figure 1). abnormalities in social interaction. The cognitive symptoms refer In nonhuman primates, success in executive tasks require to inability to organize one’s life and to work sequentially and optimal dopamine signaling (Brozoski et al., 1979), suggesting effectively. Although positive symptoms are the most dramatic that cognitive dysfunction in schizophrenia involves disturbance and characteristic symptoms of schizophrenia, they are greatly of the dopamine system. This is one of many indirect observa- improved with antipsychotic medication, whereas the negative tions consistent with the dopamine hypothesis of schizophrenia,

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Figure 1. Tasks Used to Measure Prefrontal- Wisconsin Card Sorting Task (WCST) Cortex-Dependent Cognitive Executive Function Measures: Flexibility, attentional set shifting. in Humans Subjects must sort cards by a single feature (e.g., colour) and then, without instruction, 'shift set' to sort them by a different category (e.g., shape or number)

N-Back Test Measures: executive control of the updating of that hypofunction of the prefrontal cortex information in working memory contributes to the cognitive symptoms (Buchs- Subjects are presented with a series of stimuli and must baum et al., 1982; Farkas et al., 1984; Ingvar determine if the one currently presented stimulus matches one that has been presented one (1back), two (2-Back) and Franze´ n, 1974a, 1974b; for review, see Lid- or three (3-back) positions previously in the stream. dle et al., 1992; Ragland et al., 2007). Functional Stroop Tests imaging studies (fMRI) also document a further Measures: flexibility, resistance to interference hypofrontality in schizophrenia. During the Wis- In the Color Task subjects must read aloud a list of color names which are printed in a non matching color. In the consin Card Sorting Test (Weinberger et al., Color-Word Task, the subject must name the 1986), patients with schizophrenia show color of ink in which the color names are printed. a decrease in regional cerebral blood flow in Tower of London the frontal cortex compared to healthy controls. Measures: Problem solving, strategy Planning These alterations in prefrontal activation have Subjects must move colored disks one at a time from an initial arrangement to match a goal arrangement. now been demonstrated during a variety of Subjects are instructed to plan the sequence of moves tasks for executive function. It is thought that hy- before carrying them out so that they achieve the goal Start Goal arrangement in as few moves as possible. poactivation of the dorsolateral prefrontal cortex may be accompanied by compensatory hyperactivation of directly adjacent regions, re- the most enduring and continually provocative hypothesis in flecting a disturbance in the ability to engage the functional psychiatric research. networks subserving executive functions (Barch, 2005; Glahn et al., 2005; Ragland et al., 2007). There is no unequivocal evidence for a cortical dopamine The Original Dopamine Hypothesis of Schizophrenia hypofunction in schizophrenia; the relationship between meta- Based on seminal experiments by Arvid Carlsson and others bolic function and dopaminergic activity is as yet indirect and studying the effects of antipsychotic medications, Jacques conjectured. However, there are several lines of evidence that Van Rossum proposed, in 1966, that ‘‘overstimulation of dopa- suggest that cortical dopamine hypofunction relates to the mine receptors could be part of the etiology’’ of schizophrenia cortical functions affected in patients with schizophrenia. Here (for a historical review, see Baumeister and Francis, 2002). we describe six such independent lines of evidence, which Today, there is no question that intervention in the dopaminergic provide indirect support for the hypothesis that the metabolic system is successful in treating the positive symptoms of schizo- hypofunction of the prefrontal cortex observed by MRI might phrenia. All established antipsychotic medications antagonize involve dopamine dysregulation. (1) In animal studies, pioneered dopamine D2 receptors, and their clinical efficacy correlates by Pat Goldman-Rakic, dopamine signaling was identified as directly with their occupancy of D2 receptors (Seeman et al., important for cognition mediated by the prefrontal cortex. Deple- 1975; Creese et al., 1976). However, the clinical efficacy of any tion of dopamine in the prefrontal cortex impairs working drug does not necessarily imply that its target is involved in an memory in nonhuman primates (Brozoski et al., 1979), as does etiological mechanism, and as already stated, D2 blockade blockade of dopamine D1 receptors in the PFC (Vijayraghavan does not ameliorate all symptoms. But independent of antipsy- et al., 2007; Williams and Goldman-Rakic, 1995). (2) Genetic chotic actions, there is evidence (to be described below) that studies support the idea that dopamine levels in the prefrontal dopamine dysfunction could be involved in the pathogenesis cortex affect cognitive function also in humans. A common of the disease. polymorphism in one of the enzymes that break down dopamine, The original dopamine hypothesis did not attempt to distin- the gene encoding catechol-O-methyl transferase (COMT), guish between the three major dopaminergic pathways that results in altered activity of the enzyme and presumably in the were identified using the Falck-Hillarp method: the mesostriatal, level of dopamine available at the synapse. In healthy subjects, the mesolimbic, and the mesocortical (Moore and Bloom, 1978) the polymorphism modulates performance in the tests of (Figure 2). As a result, the original version of the hypothesis working memory and executive function that are significantly viewed schizophrenia as a general dopamine hyperfunction affected in patients with schizophrenia (Bruder et al., 2005; syndrome (Figure 1B). Egan et al., 2001). In fact, a meta-analysis of such studies, including 12 published reports, concluded that there is a signifi- A Reconceptualization of the Dopamine Hypothesis cant effect of this COMT genotype on executive function, specif- of Schizophrenia ically performance in the Wisconsin Card Sorting task, in healthy Consistent with the potential importance of the frontal lobe first individuals (Barnett et al., 2007). (3) In patients with schizo- proposed by Kraepelin, the majority of brain imaging studies of phrenia, a decrease in the immunoreactivity for both tyrosine patients with schizophrenia using both MRI and PET suggest hydroxylase, the dopamine synthetic enzyme, and for the

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A PFC B PFC C PFC D PFC

dSTR dSTR dSTR dSTR D2R

vSTR vSTR vSTR vSTR

SNc SNc SNc SNc

VTA SNr VTA SNr VTA SNr VTA SNr

Nigrostriatal and mesocortical The original A revised Results of brain midbrain dopaminergic dopamine hypothesis dopamine hypothesis imaging studies in projections of schizophrenia of schizophrenia schizophrenia

Dorso-medial DA cells project to ventro-medial striatum. Ventral tier densocellular DA cells project to medial striatum Ventro-lateral DA column cells project to dorso-lateral striatum

Figure 2. The Dopamine Hypothesis of Schizophrenia (A) Organization of the nigrostriatal and mesocortical midbrain dopaminergic projections. The dopaminergic midbrain neurons topographically project to the striatum but with an inverse dorsal-to-ventral organization. The mesocortical projections arise from the dorsal and medial dopamine cells. (B) The original dopamine hypothesis of schizophrenia. The original dopamine hypothesis proposed that a global hyperactivity of the dopaminergic projections in the brain may lead to the symptoms of schizophrenia. (C) The revised dopamine hypothesis of schizophrenia. The revised dopamine hypothesis proposed that a hyperactive nigrostriatal dopaminergic projection leads to positive symptoms but a hypoactive mesocortical projection is responsible for cognitive and negative symptoms. (D) Results of brain imaging studies in schizophrenia. Brain imaging studies show that an increase in amphetamine-induced dopamine release in the striatum is highest in the associative striatum. Moreover, the density and occupancy of striatal D2 receptors is increased in drug-free or drug-naive patients. PFC, prefrontal cortex; dSTR, dorsal striatum; vSTR, ventral striatum; VTA, ventral tegmental area; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; D2R, dopamine D2 receptor. dopamine transporter (Akil et al., 1999) has been found in the according to which the three major dopaminergic pathways prefrontal cortex in the brains of patients with schizophrenia at are not affected in similar ways in the disease. They proposed post mortem. This finding still awaits replication, however. (4) that only the mesostriatal and mesolimbic pathways became In the cerebral spinal fluid of patients with schizophrenia, the hyperactive and that these mediate the positive symptoms of basal concentration of the dopamine metabolite homovanilic schizophrenia. They further suggested that the hyperactivity in acid correlates with the regional cerebral blood flow induced these two pathways is secondary to a hypofunction of the by mental activity in the PFC (Weinberger et al., 1988; Kahn prefrontal dopamine system that is responsible for the cognitive et al., 1994). This suggests that in patients the level of prefrontal deficits (Davis et al., 1991; Weinberger, 1987)(Figure 2C). dopamine release could predict prefrontal function (Weinberger Although this model for the pathogenesis of schizophrenia has et al., 1988; see also Elsworth et al., 1987). Future imaging been supported by animal models, there is as yet no direct studies that directly measure dopamine release in the cortex evidence derived from studies with patients. There are in fact are needed to further support this idea. (5) An increase in D1 alternate and equally valid reasons to suggest that if dopami- receptor density has been found in the prefrontal cortex of nergic dysfunction is causative in the pathogenesis of schizo- patients with schizophrenia using [11C]NNC as a D1-specific phrenia the deficits may occur in the opposite order. We here PET ligand. This increase in receptor availability, which was discuss the possibility that the striatum may have a primary not observed using the earlier tracer [11C]SCH 23390 (Okubo role in the pathogenesis of schizophrenia and that the striatum et al., 1997), correlates with deficits in the N-back task (Abi- plays a critical role in initiating the cognitive deficits. We present Dargham et al., 2002) and could be a compensation for the evidence for a dopamine hyperfunction in the striatum of patients hypoactive cortical dopaminergic projections. (6) A PET study with schizophrenia and show how this hyperfunction might also using the tracer [11C]NNC showed that the COMT genotype specifically contribute to the cognitive deficits of schizophrenia. presumed to enhance dopamine metabolism predicts cortical- limbic D1 receptor availability (Slifstein et al., 2008). A Dopaminergic Hyperfunction in the Striatum as Causal To reconcile the more recent evidence for dopamine hypoac- in the Cognitive Deficits of Schizophrenia tivity in the frontal cortex with the original hypothesis of a general The idea of hyperactive subcortical dopamine in schizophrenia hyperdopaminergia syndrome, Weinberger and Davis proposed was originally based on the efficacy of antipsychotic medication, a variant of the original dopamine hypothesis of schizophrenia, but this idea has now been supported by a number of important

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findings, which converge on evidence for both an increase in amine-induced dopamine secretion in patients with schizo- striatal dopamine and an increase in striatal dopamine receptors. phrenia is most pronounced in the dorsal or associative striatum, (Figure 2D). Evidence for increased dopamine release in the the region also known as the head of the caudate nucleus. These striatum came from several sources. For example, some, though findings were surprising because animal models had suggested not all, post mortem studies have detected an increase in the that antipsychotic medication improves positive symptoms by level of dopamine in the striatum or an increase, even in unmed- acting on the ventral striatum, the nucleus accumbens, rather icated patients, in the levels of the dopamine metabolite HVA than the dorsal striatum, the caudate nucleus. (for a review, see Davis et al., 1991). This is consistent with the To date there are no ways for determining whether patients numerous findings of an increase in striatal uptake of dopamine with schizophrenia have excess D2 receptors during develop- in patients with schizophrenia, as determined by an increase in ment. But, if striatal dopaminergic hyperactivity is a causative the uptake of Fluoro-Dopa, by the dopamine-synthesizing event in the disease process, then variants in genes coding for enzyme L-amino acid decarboxylase (Frankle, 2007; Hietala components of dopamine signaling may be associated with et al., 1999; Hietala et al., 1995; Lindstro¨ m et al., 1999; Meyer- schizophrenia. Indeed, genetic studies have identified associa- Lindenberg et al., 2002; Reith et al., 1994). Similarly, PET imaging tions between variations in genes involved in dopamine signaling has also found that in patients with schizophrenia, there is an and schizophrenia (Allen et al., 2008; Talkowski et al., 2008). The increase in the striatum of amphetamine-induced displacement continually updated meta-analyses of published schizophrenia of D2 receptor binding, consistent with increased dopamine association studies, which currently include over 1400 studies, release (Abi-Dargham et al., 1998; Breier et al., 1997; Laruelle continues to put the D2 receptor gene (DRD2) in the top ten et al., 1996). ‘‘most strongly associated genes’’ (Allen et al., 2008). Of the These alterations in dopamine availability are paralleled by six individual SNPs in the D2 receptor gene subjected to the changes in striatal dopamine receptors. First observed by Cross meta-analysis, rs2677 (C957T) has the highest odds ratio of et al. (1981) and then by others (for a review, see Davis et al., 1.37. This SNP does not affect the amino acid sequence of the 1991), an upregulation of striatal D2 receptors was discovered protein, but the C allele increases mRNA stability (Duan et al., in post mortem studies of patients who were drug-free. Similarly, 2003) and has now been associated with schizophrenia in five an increase in the density and occupancy of D2 receptors in the independent studies (Betcheva et al., 2009; Ha¨ nninen et al., striatum has been found in PET imaging (Abi-Dargham et al., 2006; Hoenicka et al., 2006; Lawford et al., 2005; Monakhov 2000; Seeman and Kapur, 2000; Wong et al., 1986; Laruelle, et al., 2008). There are also two studies that did not find a signif- 1998). Although there has been inconsistency in these findings, icant association (Gupta et al., 2009; Sanders et al., 2008). In the inconsistency seems to be related to the functional proper- healthy subjects, the C allele is negatively associated with cogni- ties of the different ligands that have been used. For example, tive performance in the Wisconsin Card Sorting Test, linking D2 M-spiperone is more lipid soluble and more readily penetrates receptor function with cognition (Rodriguez-Jimenez et al., cell membranes to reach internalized receptors than do the ben- 2006). Moreover, this allele interacts with the Val158Met poly- zamides that generally are water-soluble. These different classes morphism in the COMT gene in the six-word serial position of ligands may also differ in their binding to monomeric versus task, a test of working memory (Xu et al., 2007). While genetic dimeric receptors (Seeman and Kapur, 2000). Moreover, data do not support a role for any individual SNP as a significant elevated occupancy of D2 receptors was found to be predictive causative agent in schizophrenia, these data may imply that for a good treatment response of positive symptoms with anti- genetic variation in the D2 receptor could contribute to the psychotic drugs (Abi-Dargham et al., 2000). Although antipsy- disease and therefore warrant continued investigation. In further chotic medications increase the density of D2 receptors in the support of a genetic component to D2 receptor upregulation, striatum, thereby complicating the interpretations of the PET unaffected monozygotic co-twins of patients with schizophrenia imaging studies, a mild (12%) but highly significant elevation in show increased D2-receptor density in the caudate (Hirvonen D2 receptor binding potential has also been observed in drug- et al., 2005). free and drug-naive patients (see meta-analysis: Laruelle, 1998). In summary, considerable evidence has accumulated for An increase in D2 receptor binding potential does not, a specific hyperdopaminergic state in the striatum of patients however, necessarily imply an increase in the number of recep- with schizophrenia. Because the striatum is involved in aspects tors—it could also be due to an increase in the affinity of the of cognition and, as we discuss in the next section, the prefrontal receptors (Seeman et al., 2006). To clarify this issue, studies cortex and the striatum are anatomically interconnected, it raises using D2 receptor ligands that preferentially bind to D2 receptors the interesting possibility that the striatum may be involved in the high-affinity state are needed. In addition, there is a need to directly in cognitive functions traditionally thought of as strictly determine whether the binding potential of D2 receptors is mediated by the prefrontal cortex. To examine this possibility already high in patients in the prodromal phase of the disease, further, we review the evidence for the direct role of the striatum and during remission, or whether the phenotype fluctuates with in cognitive domains related to the deficits in schizophrenia. the phase of the illness, like the observed increase in amphet- amine-induced dopamine. This would have important implica- The Striatum Has an Important Role in Cognition tions for the role of striatal D2 receptor binding in the etiology The striatum, which is made up of the caudate and the putamen, of the disease. is the input component of the basal ganglia, a group of subcor- With the improved resolution of PET imaging, Kegeles et al. tical nuclei that traditionally has been associated with the control (2006) have been able to determine that the increase in amphet- of motor movement. The striatum receives its inputs from the

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cortex, the thalamus, the hippocampus, and the amygdala. The caudate nucleus). Consequently, lesions of either the prefrontal main output nuclei of the basal ganglia are the globus pallidus, cortex or the dorsal striatum impair working memory (Battig the subthalamic nucleus, the substantia nigra, and the ventral et al., 1960; Divac et al., 1967). Additional evidence for a function tegmental area. These output structures mainly project to the of the striatum in working memory comes from physiological thalamus, the principal target of the basal ganglia. The thalamus studies. Neurons that show increased activity during the delay projects back to the cortex, thereby completing a loop that period of a working memory task may code for the actual memory involves the cortex, the striatum, and the thalamus (Alexander or associated attentional or motivational information. These et al., 1986). The main reason that the focus of study for the stria- ‘‘memory cells,’’ originally identified in the prefrontal cortex by tum has been on its role in motor control is due to the established Joaquin Fuster (Fuster, 1973), have also been found in the importance of the striatum in the pathophysiology of Parkinson caudate nucleus and other areas of the cortex (Hikosaka et al., and Huntington disorders, two neurodegenerative diseases 1989). In rodents, the homologous ‘‘associative loop’’ includes that affect motor control. The striatum is recruited for the refine- the medial prefrontal cortex and the dorsomedial striatum (the ment of motor actions with the procedural learning of motor medial caudate putamen). Lesioning this region of the striatum habits. As a result, after extensive numbers of trials, performance affects spatial working memory (Mair et al., 2002; Voorn et al., becomes insensitive to changes in the expected reward values 2004) in the same way that lesions of the prefrontal cortex do. (Graybiel, 2005). Patients with schizophrenia show subtle defi- Lesions of the striatum or its associative loops also affect various cits in these types of behaviors, suggesting an impairment in attentional processes. In the Five-Choice Serial Reaction Time striatal function (Horan et al., 2008; Siegert et al., 2008). This Task, which measures attention in rodents, lesions of either the impairment is mild, however, compared to the deficits observed dorsomedial prefrontal cortex or the medial caudate putamen in Huntington and Parkinson disorders, whose phenotypes are reduce response accuracy and increase premature and persev- comparable to those produced in animal models by extensive erative responding, implicating the striatum in attention and lesions of the striatum. cognitive control (Chudasama and Robbins, 2006). A function Work in monkeys and rats beginning in the 1960s by Steven of the striatum in attentional processes and cognitive control is Chorover, Haldor Rosvold, and others showed that lesions in further suggested in humans because attentional set shifting the dorsal striatum not only affect procedural learning but also measured within the Wisconsin Card Sorting Task activates the result in cognitive deficiencies similar to those produced by caudate nucleus in healthy human subjects (Rogers et al., 2000). prefrontal lesions (Battig et al., 1960; Chorover and Gross, These findings suggest that the prefrontal cortex and the stria- 1963). Detailed anatomical tracing studies revealed that within tum function in concert to mediate working memory and other the corticostriatal pathways there are two types of projections executive functions. The finding that the cognitive deficits in from the prefrontal cortex to the dorsal (associative) striatum: schizophrenia may arise not simply from alterations in the focal, circumscribed projections and diffuse, widespread projec- prefrontal cortex but also from a deficit in the functioning of the tions (Eblen and Graybiel, 1995). The focal projections to the striatum places the nature of the cognitive symptom in a new associative striatum (the head of the caudate) include some light. In this regard it is interesting that the increase in amphet- areas of convergence between terminal fields from different amine-induced dopamine secretion in patients with schizo- functional regions of the prefrontal cortex, such striatal nodes phrenia is most pronounced in the associative striatum (Kegeles may therefore be critical for integrating information encoded in et al., 2006), the area of the striatum that receives direct input the cortex (Calzavara et al., 2007; Graybiel, 1998; Reep et al., from the dorsolateral prefrontal cortex. Therefore, increased 2003). Consistent with this idea, Ann Graybiel has found that dopamine release in the caudate may have a direct modulatory information derived from the cortex is transformed in the stria- effect on the efficacy of the corticostriatal synapse in the asso- tum, where representations of motor and cognitive action ciative striatum, potentially affecting cognitive processes such sequences can be integrated and developed into more complex as working memory or attentional-set shifting. units for implementing more efficient behavioral responses If indeed the corticostriatal pathway is critical in the generation (Graybiel, 1998). In vivo recordings reveal dramatic learning- of cognitive symptoms of schizophrenia, it may be that compo- related changes in striatal neuronal activity as animals learn nents of the loop are disabled in a particular etiological procedural tasks requiring conditional associations (Barnes sequence. A primary defect in the cortex has been proposed, et al., 2005; Jog et al., 1999). Taken together, these results, but direct evidence is lacking. It may therefore be interesting to and those obtained with in vivo imaging in nonhuman primates investigate the possibility that the striatum is the primary site of (Levy et al., 1997) and human subjects provide strong evidence dysfunction. This idea is an elaboration of the previous sugges- that, in addition to modulating motor control and motor learning, tion that the striatum and associated basal ganglia are cognitive the striatum plays an important role in the formation of more pattern generators working in concert with the prefrontal cortex complex behaviors, including decision making and executive to allow new cognitive patterns to form and that a deficit in this function (Graybiel, 2008). striatum-based function may be a core defect in schizophrenia In retrospect, this view is not surprising. As we have seen, the (Graybiel, 1997). The hypothesis that a primary defect originates striatum and cortex are anatomically and functionally linked in the striatum rather than the cortex, does not imply that the by means of several parallel frontostriatal associative loops striatal deficit is necessarily more profound than the defect in (Alexander et al., 1986). In primates, the ‘‘associative loop’’ the cortex. As we have mentioned, the cognitive behaviors that projects from the dorsolateral prefrontal cortex directly to the are sensitive to striatal lesions, such as habit learning and implicit associative component of the dorsal striatum (the head of the memory, are less affected in schizophrenia than executive

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functions, and this may be because they are less sensitive to the dopamine D2 receptor numbers (Pycock et al., 1980). Similar modulation of dopamine. observations have been made in primates (Roberts et al., 1994), suggesting that prefrontal dopaminergic hypofunction Testing the Specific Hypothesis that Striatal can indeed induce a hyperactive subcortical dopamine system. Dysfunction Can Result in Cognitive Deficits Related However, studies with genetically modified mice have recently to Those Observed in Schizophrenia: The Use of Mouse presented evidence that modulation in the opposite direction is Models also possible. The finding that hypodopaminergic function in the cortex and To address the causal relationship between striatal dopamine hyperdopaminergic function in the striatum coexist in patients dysfunction and cognition and to test the specific hypothesis with schizophrenia poses a number of questions. Does a single that striatal D2R hyperactivity can result in the cognitive deficits common primary etiologic factor drive both dopaminergic observed in schizophrenia, Kellendonk et al. generated a genet- dysfunctions? Or does one perturbation drive the other? For ically modified mouse that modeled the observed increase in example, the alteration in the prefrontal cortex may precede striatal D2 receptor availability, one of the specific in vivo findings that of the striatum, or the alteration in the striatum may precede of striatal dysfunction in schizophrenia (Kellendonk et al., 2006). that of the cortex. Of these three possibilities, only the second In this transgenic mouse, the expression of dopamine D2 has been formally proposed (Davis et al., 1991; Weinberger, receptors was selectively increased in the striatum, including 1987); we believe it is also important to investigate the other the caudate putamen, nucleus accumbens, and olfactory two possibilities. tubercle. To obtain temporal control of transgene expression, PET studies that combined measurement of regional cerebral the mice were created using the bi-transgenic tetracycline- blood flow in the prefrontal cortex and F-Dopa uptake in the sensitive expression system (Mayford et al., 1996). Striatal D2 striatum have found that prefrontal hypofunction correlates overexpressing mice show an impairment in prefrontal-depen- with increased F-Dopa uptake in the striatum, suggesting that dent cognitive tasks that are associated with schizophrenia as both are functionally linked (Meyer-Lindenberg et al., 2002). well as a decrease in dopamine turnover and an increase in D1 While PET studies are powerful in detecting differences in patient receptor activation in the prefrontal cortex (Bach et al., 2008; populations, they do not establish causality and therefore cannot Kellendonk et al., 2006). These results suggest that a selective be used to identify the origins of these dysfunctions. It may be and primary increase in dopamine signaling restricted to the highly informative of the etiology of schizophrenia if we could striatum can result in deficits in both the cognitive behaviors identify any sequential events that could be predicted to unfold affected in schizophrenia and in the perturbation of the prefrontal into schizophrenia. Some insights into the question could cortical dopamine system. Most interestingly, the cognitive defi- come from studying prodromal patients. Cognitive deficits cits persisted long after expression of the transgene had been begin to emerge in the prodromal period years before the full switched off. In fact, expression during development was suffi- onset of the disease in the patient. The early emergence of cient to cause cognitive deficits in adulthood. cognitive symptoms has given rise to the idea that the prefrontal These findings suggest two important new ideas. First, abnormality may occur earlier than the other symptom clusters. a hyperfunctioning of the mesostriatal pathway could be an early However, as we have seen, because the preservation of the event in the etiology of the disease, but this hyperfunction gives corticostriatal synapses is essential for prefrontal cognitive rise to compensatory changes in the prefrontal cortex that are functions, it may be impossible to use symptomatology to isolate induced during development and maintained even after treating the origin of the pathology. Evidence supporting an early pertur- the mesostriatal hyperactivity. Second, the reason D2 receptor bation has been found in both the prefrontal cortex and the blockade has minimal, if any, beneficial effects on the cognitive striatum. MRI has identified a reduction in frontal gray matter symptoms of schizophrenia is because antipsychotic medica- volume in patients at risk for schizophrenia (Borgwardt et al., tions are given too late, long after irreversible compensatory 2007). As expected, this reduction is milder than that observed changes have taken place. in schizophrenic patients. Evidence for early hyperactivity of How the increase in developmental D2 receptor expression the striatal dopamine system comes from a recent imaging study produces these phenotypes may therefore be highly informative that found that the uptake of F-Dopa is already increased in the for the possible pathophysiological steps in the development of striatum of prodromal patients (Howes et al., 2009). On a behav- the disorder. We will now discuss, in turn, how altered subcor- ioral level, subtle abnormalities in motor as well as cognitive and tical dopamine may impact the functioning of both the striatum emotional development have been observed in children who and the prefrontal cortex. later develop schizophrenia (Isohanni et al., 2005; Mittal et al., 2008; Walker et al., 1994), pointing to an early involvement of The Possible Consequences of Altered Subcortical both structures in the disease. Dopamine on Striatal Function One useful and direct way for exploring causal mechanisms in Several lines of evidence suggest that alterations in the subcor- the pathophysiology of disease comes from animal models. tical dopamine system affect the global functioning of the These can prove specifically useful here because they allow striatum, producing both metabolic and structural changes. perturbations that assist the investigation of the mechanisms Decreased metabolic activity in the basal ganglia and the stria- by which schizophrenia might possibly develop (Kellendonk tum (caudate nucleus) has been consistently found by PET et al., 2009). In rats, dopamine depletion induced in the prefrontal imaging studies in unmedicated patients (for review, see Buchs- cortex by 6-OHDA increases subcortical dopamine turnover and baum and Hazlett, 1998). In contrast, in patients treated with D2

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A B C Figure 3. Three Potential Cellular Mechanisms by which Increased Striatal PFC PFC PFC Dopamine Transmission via D2 Receptors Could Affect Striatal Function in Patients with Schizophrenia (A) Heterosynaptic inhibition of corticostriatal termi- nals. It has been shown that activation of D2 recep- GLU GLU tors at the presynaptic terminal of the incoming D2R STR ChAT cortical projections inhibits corticostriatal gluta- STR STR D2R MSN MSN D2R mate release. Heterosynaptic inhibition is selective for the least active terminals, thereby filtering out DA DA DA less active inputs (Bamford et al., 2004). Because PET imaging does not have the resolution to deter- mine which exact cells contribute to the elevated SNc SNc SNc binding potential of D2 receptors in the striatum, D2 receptors could be upregulated in the VTA VTA VTA corticostriatal terminals. This in combination with SNr rNS rNS increased dopamine release may lead to a hyperef- fective heterosynaptic inhibition that may prevent Heterosynaptic inhibition of Inhibition of medium spiny Global inhibition of medium the transmission of important cognitive information cortico-striatal terminals neurons of the direct pathway spiny neurons from the cortex to the striatum. (B) Inhibition of medium spiny neurons of the direct pathway. Both D1 and D2 receptors are present on medium spiny neurons, which represent 95% of striatal neurons and are the main output neurons of the striatum. D1 receptors are preferentially present on medium spiny neurons that project directly to the substantia nigra pars reticularis and the internal segment of the globus pallidus. D1 receptor activation enhances excit- ability of these cells. In contrast, D2 receptors are preferentially expressed on medium spiny neurons that project indirectly to the substantia nigra pars reticularis and the internal segment of the globus pallidus. D2 receptor activation reduces excitability of these cells (Surmeier et al., 2007). Upregulation of D2 receptors may therefore affect the balance between direct and indirect pathways and alter the striatal output of the incoming cortical information. (C) Global inhibition of medium spiny neurons. Activation of D2 receptors on the cholinergic interneurons diminishes acetylcholine release from these cells. The released acetylcholine affects glutamatergic and dopaminergic terminals. Acetylcholine generally enhances the glutamatergic excitation of medium spiny neurons (Surmeier et al., 2007). Increased activation of D2 receptors on cholinergic interneurons may therefore globally reduce the excitability of the striatum. Although the mechanism for the reduced metabolic activity observed in patients with schizophrenia is unknown, reduced cholinergic activity could be a contributing factor. MSN, medium spiny neuron; ChAT, choline-acetyl-transferase as a marker for cholinergic interneurons; GLU, glutamate; DA, dopamine.

receptor antagonists, there is an increase in striatal glucose synaptic density decreases (Andreassen et al., 2001; Roberts metabolism (Buchsbaum and Hazlett, 1998; Buchsbaum et al., et al., 1995). 1992; Shihabuddin et al., 1998). These two findings suggest If a reduction in striatal volume is indeed an early event in the that D2 receptor activity negatively controls striatal metabolic development of the disease, or an underlying risk trait, then it rate (see Figure 3, which discusses how overstimulation of stria- may be highly valuable to measure striatal volume in individuals tal D2 receptor alters physiology on the cellular level [Bamford identified to be in the prodromal phase of the disease. It has et al., 2004; Surmeier et al., 2007]). Data from mice that selec- already been shown that young offspring of patients with schizo- tively overexpress D2 receptors in the striatum support this phrenia show reduced striatal volumes compared to young idea. D2 transgenic mice show decreased glucose metabolism people with no family history of mental illness (Rajarethinam in the striatum, phenocopying the finding in unmedicated et al., 2007). This finding suggests that reduced striatal volume patients (Kellendonk et al., 2006). Switching off the additional is a genetic risk factor or perhaps even an early marker, since transgenic receptor expression in the adult animal returned a significant proportion of the at-risk group are expected to glucose metabolism to normal levels, suggesting that the develop schizophrenia. A replication of this study would also changes in metabolism were due to concurrent D2 receptor add weight to the hypothesis of early involvement of the striatum. activity and not due to a developmental compensatory change. More importantly, longitudinal studies of individuals with high Chronic alterations in dopamine signaling and neuronal genetic risk from an even earlier age could determine when metabolism may lead to structural changes. In most structural during development the differences in striatal volume become MRI studies of patients with schizophrenia, there is an increase apparent (Rajarethinam et al., 2007). in striatal volume (Shenton et al., 2001). These increases appear to be a consequence of medication, because never-medicated How Can Striatal D2 Receptors Affect the Functioning patients have smaller caudate nucleus (Keshavan et al., 1998; of the Prefrontal Cortex? Shihabuddin et al., 1998), and longitundinal studies have found There are at least three possible ways by which altered dopa- that first-episode patients that are treated with neuroleptics mine signaling in the striatum could lead to prefrontal-dependent show increases in striatal volumes within 12–18 month (Chakos cognitive deficits. First, dopamine signaling may disrupt or alter et al., 1994; Keshavan et al., 1994). We have made similar obser- the cognitive information that is coming in from the cortex. As vations in D2 receptor overexpressing mice, which, like unmed- discussed, the striatum and cortex are anatomically and func- icated patients, show decreased striatal volume (unpublished tionally linked via several parallel frontostriatal loops, and in addi- data). This is consistent with the observation that, when rats tion, nodes of convergence exist to which different cortical areas are treated chronically with the D2 blocker haloperidol, striatal project (Calzavara et al., 2007; Eblen and Graybiel, 1995; Reep volume and the area of neuronal terminals increase whereas et al., 2003). One such node is located in the associative

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Figure 4. Mechanisms on the Circuit Level ABPFC PFC C PFC by which Increased Striatal Dopamine Transmission via D2 Receptors Could Lead  dSTR  dSTR dSTRdS to Cognitive Deficits (A) Striatal disruption. The striatum and cortex are D2R D2R D2R anatomically and functionally linked via several parallel frontostriatal loops. Neuronal information encoding working memory and executive function may be altered by increased D2 receptor signaling vSTR vSTR vSTR THALAMUS at the level of the medium spiny neuron in the asso- ciative striatum, which is one synapse down- stream of the dorsolateral prefrontal cortex. SNc SNc SNc (B) Striatal modulation of prefrontal function via the dopaminergic system. The striatum harbors VTA SNr VTA SNr VTA SNr the main input to the dopaminergic neurons of the ventral tegmental area (VTA) and substantia nigra (SN). By modulating the activity of neurons in the Modulation of PFC via the Modulation of PFC via the VTA, it may modulate the dopaminergic input of Striatal disruption dopamine system thalamus the prefrontal cortex. In mice with upregulated D2 receptors in the striatum, prefrontal dopamine Dorso-medial DA cells turnover is decreased and D1 receptor activation Ventral tier densocellular DA cells increased. Since optimal D1 receptor activation Ventro-lateral DA column cells in the prefrontal cortex is crucial for working memory, this could be a mechanism by which Substantia nigra reticularis, GABA neurons striatal D2 receptor overactivation may affect prefrontal function. (C) Striatal modulation of cortical function via the thalamus. The striatum projects back to the prefrontal cortex via the thalamus and may thereby modulate activity in the prefrontal cortex (for simplicity only the direct pathway via the substantia nigra reticularis is drawn). These mechanisms on the circuit level could already arise during development. In mice, selective upregulation of D2 receptors in the striatum during development leads to prefrontal-dependent cognitive deficits that cannot be reversed by switching off the additional receptors in the adult animal. This suggests that early upregulation of D2 receptors during development leads to compensatory changes potentially in the discussed circuits that cannot be easily reversed in the adult animal. striatum, which is where the increase in amphetamine-induced molecules at any time point and look at the effect at anytime dopamine release has been observed in patients with schizo- point after. For example, in the striatal D2R overexpression phrenia. The associative striatum receives input from the dorso- model, it is possible to quantify the neuronal projections in the lateral prefrontal cortex and the orbitofrontal cortex (Eblen and corticostriatal pathway using quantitative tracing techniques. Graybiel, 1995; Haber et al., 2006). Increased D2 receptor Such experiments, combined with immunohistochemistry, may signaling at the level of the medium spiny neuron in the associa- identify specific cell types and molecular markers involved in tive striatum may therefore disturb the integration of neuronal any circuit abnormalities, and the relevance to schizophrenia of information coming from different areas of the prefrontal cortex such markers may be investigated by studying them in post (Figure 4A). mortem tissue. Other novel mouse models that could be infor- Second, the striatum is the main structure projecting to the mative might include those that express cell-type-specific, easily dopaminergic midbrain neurons in the ventral tegmental area imaged markers, which would allow for the monitoring of cortico- (Frankle et al., 2006). Increased signaling through striatal D2 striatal projections as they develop. Such marker mice could be receptors may regulate the activity of the dopaminergic neurons, subjected to the numerous pre-, peri-, or postnatal alterations, including those that project to the cortex, thereby affecting including environmental insults that have been determined to dopamine release in the prefrontal cortex (Figure 4B). Third, influence risk for schizophrenia, and one could then see when altered activity in the striatum could indirectly change cortical and how such perturbations affect development of the tagged functioning via the thalamus, which is part of the parallel cortico- circuit(s). Separate cohorts of mice that have not been sacrificed striatal loops (Figure 4C). for imaging could be allowed to develop and their adult cognitive The data from these genetically modified mice suggest that functions measured. By using different developmental insults mechanisms on the circuit level that in principle could contribute and inducing them at different time points in development, one to the cognitive symptoms of schizophrenia already emerge presumes that subtly different anatomical phenotypes will during prenatal development. In these mice, the selective upre- ensue. A systematic comparison of the anatomical and cognitive gulation of D2 receptors in the striatum during development defects might allow one to make more detailed inferences about leads to prefrontal-dependent cognitive deficits that cannot be the relative importance of specific pathways on specific cogni- reversed by switching off the additional receptors in the adult tive functions. By combining such studies with quantitative animal (Bach et al., 2008; Kellendonk et al., 2006). assays of gene or protein expression, specifically in the tagged Perhaps the most useful direction in which to take the animal cells, new candidate molecules may be identified, which one model approach is to study developmental mechanisms that could study in post mortem tissue to determine if similar changes are extremely difficult to study in humans. Increasing our under- in expression occur in the brains of patients with schizophrenia. standing of the changes in early development that result in One limitation of the approach is that some of the expression cognitive dysfunctions in adulthood would be a major step changes identified may occur only during development and forward. In mouse genetic models, we can perturb individual therefore be undetectable in post mortem studies.

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Conclusion shown to be efficacious in preclinical models of the positive, We begin our conclusion with an open disclaimer. To focus negative, and cognitive symptoms of schizophrenia (Grauer attention on the striatum, a relatively neglected area in schizo- et al., 2009), and one PDE10A inhibitor is currently undergoing phrenia research, the discussion presented here focuses on clinical trial. A recent comprehensive review of the potential of a specific hypothesis. Thus, this perspective is not aimed to be PDE10A inhibitors has recently been published (Chappie et al., a comprehensive review of the entire literature of schizophrenia 2009). Forty years after the dopamine hypothesis of schizo- research but rather aimed to bring more attention to a possible phrenia was first proposed, we are now in a position to benefit role of the striatum in schizophrenia. While there is solid evidence from a substantial investment in understanding the different for the involvement of the striatum, the vast majority of studies dopamine pathways in molecular terms, in the healthy and so far have focused on the prefrontal cortex and hippocampus. diseased brain. Indeed, we have not described important studies on the involve- ment of the temporal lobe (Harrison, 2004; Seidman et al., 2003). ACKNOWLEDGMENTS For example, hippocampal volume, which may be genetically determined, has been found to be reduced already at onset of We would like to thank David Lewis and Suzanne Haber for their insightful comments on an earlier version of this manuscript and Ann Graybiel for helpful schizophrenia and continues to decrease in volume as the discussions. Our research is supported by NARSAD (www.narsad.org), the disease progresses. Altered function of the hippocampus could National Institute of Mental Health Silvio O. Conte Center for Schizophrenia be responsible for some of the cognitive deficits in patients with Research (www.nimh.nih.gov), and the Lieber Center for Schizophrenia Research. We also are grateful to Harold and Shari Levy, whose generous schizophrenia, such as deficits in explicit memory. Moreover, contributions have supported our schizophrenia research. animal models suggest that hippocampal hyperactivity induces subcortical dopaminergic hyperfunction. We have deliberately REFERENCES not included these studies in this perspective. The ultimate goal of understanding the biological basis for Abi-Dargham, A., Gil, R., Krystal, J., Baldwin, R.M., Seibyl, J.P., Bowers, M., van Dyck, C.H., Charney, D.S., Innis, R.B., and Laruelle, M. (1998). Increased the cognitive symptoms of schizophrenia is threefold. First and striatal dopamine transmission in schizophrenia: confirmation in a second foremost is the development of treatments that will ameliorate cohort. Am. J. 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