Schizophrenia Research Forum - A Catalyst for Creative Thinking

Dopamine D2 Receptors Accentuate the Positive ... and the Cognitive?

24 February 2006. For years, the D2 form of dopamine receptor has been blamed for accentuating the “positive” manifestations of schizophrenia, including hallucinations and delusions. The “negative” manifestations—reduced motivation and emotional and verbal expression—and cognitive deficits—impairments in working memory and certain other domains—were thought to lie outside the D2 sphere of influence. But a paper in the February 16 Neuron suggests that neurotransmission through the D2 receptor may also exacerbate some of the cognitive deficits, at least in mice. Researchers from Eric Kandel's group at Columbia University in New York City report that behavioral inflexibility and impaired working memory, both features of schizophrenia, are evoked by even a temporary increase in the number of D2 receptors, specifically in the striatum. The findings also lend support to the idea that there is a developmental component to schizophrenia pathology.

Since it was postulated in the 1960s that dopaminergic neurons play a role in schizophrenia (see Carlsson and Lindqvist, 1963), accumulating evidence has continued to point at the D2 receptors. Some studies showed that there are more of these receptors in the striatum of schizophrenia patients, and that they are more likely to be occupied by dopamine (for a brief review, see Seeman and Kapur 2000 ). Most recently, genetic polymorphisms in the gene for the D2 receptor were linked to increased binding of dopamine and to schizophrenia itself (see Lawford et al. 2005 ; Hirvonen et al., 2004; Glatt and Jönsson, 2006). But perhaps some of the strongest evidence that the D2 receptors are important in schizophrenia comes from real-life, pharmacological data. Both typical and newer antipsychotic drugs—all D2 antagonists—relieve the positive symptoms. The newer, atypical antipsychotics, which also act on other neurotransmitter receptors, seem to be somewhat more effective against cognitive symptoms, leaving many wondering if cognitive and memory impairments are independent of any D2 receptor effects. This is what Kandel and colleagues set out to test, along with the question of whether perturbations in D2 transmission might have an early role in the pathophysiology of schizophrenia, rather than being simply a late-emerging phenomenon.

Co-first authors Christoph Kellendonk, Eleanor Simpson, and colleagues generated a transgenic mouse model in which overexpression of D2 receptors is driven by two separate promoters—the CamKIIα promoter restricts expression to the striatum and olfactory tubercle in a subset of mouse lines, and the reversible tetracycline promoter allows researchers to turn off the gene simply by adding doxycycline to the mice's chow. In adulthood, the animals had about a 15 percent increase in numbers of D2 receptors in the striatum. This is similar to the increased receptor levels seen in schizophrenia patients (see, for example, Abi-Dargham and colleagues 2000). In the mice, these additional receptors also appear to be functional because not only do the animals bind more D2 antagonists than control mice, but they also have much greater reductions in striatal adenyl cyclase activity when challenged with dopamine. This makes sense because D2 receptors are coupled to G proteins that inhibit the cyclase.

Kellendonk and colleagues put the mice through a battery of tests to determine what effect the increased striatal D2 receptor levels might have on behavior, finding a relatively specific set of abnormalities. The transgenic mice exhibited normal prepulse inhibition, a measure of sensorimotor gating that is perturbed in schizophrenia (see related SRF news story), as well as normal locomotor function, and normal behavior in a test of anxiety. However, they performed significantly poorer than control animals in several tests of working memory. Also, they were not as flexible as control mice in a task that requires them to figure out that the rules of the game have changed. Such lack of flexibility in learning paradigms is a consistently reproduced finding in people with schizophrenia.

Interestingly, even 2 weeks after the tetracycline promoter was switched off, the authors found that the animals still had difficulty in a working memory task, even though the number of D2 receptors in the striatum had dropped to levels seen in normal mice. This suggests that the deficits reflect fundamental developmental disruptions. In support of this idea, Kellendonk and colleagues found that even if they switched the transgenes off at birth, the animals still exhibited behavioral deficits when later tested. "One speculation that would arise from the D2 model is that antipsychotic drugs do not ameliorate cognitive symptoms in patients because they are given too late," Kellendonk told the Schizophrenia Research Forum.

How else do these findings relate to schizophrenia? There are numerous, though conflicting lines of evidence, linking altered dopamine transmission in the prefrontal cortex (PFC) to memory and cognitive deficits in patients, and it has been proposed that the PFC dopaminergic perturbation causes the striatal changes in schizophrenia (Weinberger, 1987). But could the causality be in the opposite direction, with extra striatal D2 receptors somehow influencing the PFC? Apparently so. Although the PFC of transgenic mice showed no morphologic abnormalities or changes of dopaminergic innervation, dopamine levels in this area were significantly increased, while dopamine metabolite levels were significantly decreased. The combination suggests a decrease in dopamine turnover. Kellendonk and colleagues also found that D1 receptor activation in the medial PFC is increased in the transgenic animals. The latter finding is of particular interest given that increased density of D1 receptors in the prefrontal cortex of schizophrenic patients has been found to correlate with deficits in working memory (Abi-Dargham et al., 2002; for discussion of conflicting findings on this point, see Guo et al., 2003 ).

While the authors caution that rodent models of schizophrenia have significant limitations, not least being that the neural circuitry in rodents is quite different from people, they also note that rodent models allow direct tests of cause-and-effect relationships. In this regard, it is significant that by introducing a single molecular alteration, which can be both spatially and temporally restricted, they have managed to recapitulate some schizophrenia-like phenotypes.

But do these mice represent an animal model for the disease? “Recent genetic studies afford a basis for optimism,” writes Solomon Snyder, Johns Hopkins University, Baltimore, Maryland, in a Neuron preview. Some of those studies have linked dopamine-related genes, such as COMT and DISC1 (see related SRF news story) to schizophrenia. “Thus, it is not all that far-fetched to envisage dopamine disturbances eliciting schizophrenic mental aberrations. In this case, the transgenic mice developed by Kellendonk and colleagues may provide a valuable tool for understanding this most malignant of mental disorders,” Snyder writes.—Tom Fagan and Hakon Heimer.

References:
Kellendonk C, Simpson EH, Poln HJ, Malleret G, Vronskaya S, Winiger V, Moor H, Kandel ER. Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning. Neuron. February 16, 2006;49:603-615.Abstract

Snyder SH. Dopamine receptor excess and mouse madness. Neuron. February 16, 2006;49:484-485.Abstract

Comments on News and Primary Papers
Comment by:  Barbara K. Lipska
Submitted 20 February 2006
Posted 20 February 2006

Kellendonk et al. have reported that transient and selective overexpression of dopamine D2 receptors in the mouse striatum during development has long-term effects on cognitive function mediated by the prefrontal cortex. This is an important study providing further elegant evidence that disturbed function of the subcortical dopamine system may affect dopamine functioning in the entire circuitry and have important adverse behavioral consequences. It is unclear, however, whether this mouse model provides us with new clues about the pathophysiology of schizophrenia. A hyperdopaminergic hypothesis of schizophrenia originated from pharmacological studies showing that dopamine D2 antagonists have antipsychotic efficacy and dopamine agonists, such as amphetamine or apomorphine, can induce psychosis (Randrup and Munkvad, 1974; Snyder, 1972). This hypothesis has been supported recently by clinical data from brain imaging studies with D2 receptor ligands showing higher presynaptic dopamine terminal activity in at least acutely psychotic patients when challenged with amphetamine or at baseline (Abi-Dargham et al., 2000; Hietala et al., 1994). Accordingly, amphetamine or apomorphine-induced hyperactivity and stereotypy in rodents have been postulated as psychosis-like behaviors and such pharmacological models have been widely used for screening antipsychotic drugs. Currently, all antipsychotic drugs on the market act by reducing D2 signals in brain, most by functioning as antagonists of D2 receptors. It is also clear, however, that although these drugs are beneficial, they do not cure the disease. It is also increasingly clear that although there is considerable evidence about the role of the dopaminergic system in the pathophysiology of schizophrenia, genetic association and linkage between schizophrenia and the genes encoding dopamine receptors or transporter remain weak (Daniels et al., 1995; Kojima et al., 1999). Thus, dopamine abnormalities may not be at the core of pathophysiology. The exploration of genetic models beyond the dopamine system may perhaps prove more fruitful for capturing many aspects of this devastating illness.

References:

Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles LS, Weiss R, Cooper TB, Mann JJ, Van Heertum RL, Gorman JM, Laruelle M. Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):8104-9. Abstract

Daniels J, Williams J, Asherson P, McGuffin P, Owen M. No association between schizophrenia and polymorphisms within the genes for debrisoquine 4-hydroxylase (CYP2D6) and the dopamine transporter (DAT). Am J Med Genet. 1995 Feb 27;60(1):85-7. Abstract

Hietala J, Syvalahti E, Vuorio K, Nagren K, Lehikoinen P, Ruotsalainen U, Rakkolainen V, Lehtinen V, Wegelius U. Striatal D2 dopamine receptor characteristics in neuroleptic-naive schizophrenic patients studied with positron emission tomography. Arch Gen Psychiatry. 1994 Feb;51(2):116-23. Abstract

Kojima H, Ohmori O, Shinkai T, Terao T, Suzuki T, Abe K. Dopamine D1 receptor gene polymorphism and schizophrenia in Japan. Am J Med Genet. 1999 Apr 16;88(2):116-9. Abstract

Randrup A, Munkvad I. Pharmacology and physiology of stereotyped behavior. J Psychiatr Res. 1974;11:1-10. Review. No abstract available. Abstract

Snyder SH. Catecholamines in the brain as mediators of amphetamine psychosis. Arch Gen Psychiatry. 1972 Aug;27(2):169-79. Review. No abstract available. Abstract

View all comments by Barbara K. LipskaComment by:  Stephen J. Glatt
Submitted 26 February 2006
Posted 27 February 2006
  I recommend the Primary Papers

The development of animal models is a critical need in the realm of schizophrenia research. Current models relying on lesions or pharmacological manipulations may be relatively nonspecific, and thus, less than optimal for unraveling the underlying pathophysiology of the disorder. Models in which specific key candidate genes are up- or down-regulated may be better models because the effects can be more subtle and, as in this study, a very specific behavioral deficit may result. Ultimately, many genes, including DRD2, may be involved in discrete aspects of the illness, and when those gene deficiencies co-occur in certain individuals, schizophrenia may manifest. This study developed and validated a model, but the study itself is a model for how such studies should be done.

View all comments by Stephen J. GlattComment by:  Daniel Weinberger, SRF Advisor
Submitted 27 February 2006
Posted 27 February 2006

The study by Kellendonk and colleagues from Eric Kandel’s lab at Columbia is a landmark piece of science in a number of respects. Transgenic overexpression of D2 receptors in the mouse striatum is a novel model of how a developmental perturbation in striatal dopaminergic signaling has long-term implications for processing of information through critical brain circuits involved in learning and memory. The model may also have implications for understanding abnormalities of the function of this circuit in schizophrenia. There is ample evidence from clinical and from postmortem studies that cortical-striatal circuits are involved as part of the pathophysiology of schizophrenia. The work of Ann Marie Thierry and colleagues in Paris in the 1970s first drew attention to the fact that cortical function impacted on the striatal dopamine system (Thierry et al., 1973). A ground-breaking study of Pycock et al. (1980) showed that DA depletion in the prefrontal cortex affected DA parameters in the striatum, by increasing specifically DA turnover and D2 receptor expression. They were the first to report an inverse relationship between cortical and subcortical DA activity, a finding that has been reproduced in a broad variety of studies in rodents, nonhuman primates, and in humans (e.g., Jaskiw et al., 1990; 1991; Deutch, 1993; Saunders et al., 1998; Bertolino et al., 1999; 2000; Meyer-Lindenberg et al., 2002; 2005). The mechanism of this effect is still uncertain, but likely involves the anatomical connectivity between prefrontal cortex and brainstem DA neurons, which involve a tonic inhibitory brake, such that normal prefrontal cortical function translates into tonic inhibition of DA neurons that project to the striatum (Carr and Sesack, 2000). Thus, prefrontal cortex is in a position to release that brake and increase DA-related reinforcement of environmental stimuli, when circumstances dictate an appropriately DA response, as might be expected during learning and memory. It is tempting to conclude from these various experiments over 30 years that the prefrontal cortex regulates the reward/reinforcement effects of DA neurons based on experiential context. The studies beginning with Thierry showed that when prefrontal function was disturbed, DA activity was no longer appropriately regulated. The study of Kellendonk et al. is consistent in terms of the circuitry involved with these earlier studies, but instead of creating an abnormality at the level of the prefrontal cortex and disrupting regulation of the DA reward system, they changed DA function directly in the striatum and their behavioral readout suggested that abnormal function of prefrontal cortex was a result. The “yin-yang” relationship again was reproduced, but now starting with the yang rather than the yin. The yang-based mechanism of the striatal effect on cortical function and cortical DA turnover is likely complex, including via striatal feedback to mesencephalic DA neurons that project to cortex and via striatal projections through thalamus back to prefrontal cortex.

The findings of Kellendonk et al. illustrate how critical prefronto-centric circuitry is, especially during development, for the elaboration of behaviors and biochemical phenomena related to schizophrenia. Their important finding that restoring normal DA function in the striatum did not restore prefrontal cognition indicates that it was no longer a matter of acute excess D2 activity in the striatum that accounted for the cognitive abnormalities. Presumably, in developmentally wiring the circuitry in and out of prefrontal cortex, abnormal information processing through the striatum (which feeds back to prefrontal cortex and presumably formats cortical information for frontally mediated action) changes the wiring diagram, producing more trait-like functional abnormalities. Trait-like changes in prefrontal function and molecular biology related to early developmental perturbations of other prefronto-centric neuronal systems implicated in schizophrenia, for example, temporal-limbic inputs to prefrontal cortex, also have been described (see Lipska and Weinberger, 2000, for review).

Finally, the study has important implications for neurobiologic models of phenomena associated with schizophrenia. PET studies of patients with schizophrenia suggest that, to the extent that striatal DA activity may be increased (Abi-Dargham et al., 1998), it is a state phenomenon, linked to active psychosis. On the other hand, evidence of abnormal cortical DA activity and function is more trait-like and persists between periods of florid psychosis. The persistent changes in cortical function independent of fluctuations in striatal D2 expression may provide some parallels to the clinical phenomena. It is surprising that these animals showed no deficits in activity or in prepulse inhibition of startle, both of which have been interpreted as measures of excess DA activity and as animal correlates of psychosis. The failure to observe these phenomena may be related to species differences—here mice as compared to earlier models with rats—or it may reflect relatively more selective overexpression of D2 receptors in the dorsal striatum. This latter finding is of interest as recent studies from Laurelle and colleagues at Columbia, using high-resolution PET imaging, have found that increased DA activity in patients with schizophrenia may also involve preferentially the dorsal striatum. The changes in DA measures in the cortex also bear interesting relationships to those found in patients with schizophrenia. The transgenic mice showed no change in markers of cortical DA innervation, which has been reported in schizophrenia (Akil et al., 1999), but they did show reduced cortical DA turnover, evidence of which also has been reported in schizophrenia (Weinberger et al., 1988). During D2 overexpression, D1 receptor sensitivity appeared to be increased, but during normalization of D2 overexpression, D1 receptors in prefrontal cortex appeared to be functionally subsensitive. These variations in cortical DA function may correspond to apparent reduced cortical DA activity as a trait characteristic and enhanced cortical DA activity as a correlate of acute psychosis (Winterer and Weinberger, 2004).

References:

Abi-Dargham A, Gil R, Krystal J, Baldwin RM, Seibyl JP, Bowers M, van Dyck CH, Charney DS, Innis RB, Laruelle M. Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiatry. 1998 Jun;155(6):761-7. Abstract

Akil M, Pierri JN, Whitehead RE, Edgar CL, Mohila C, Sampson AR, Lewis DA. Lamina-specific alterations in the dopamine innervation of the prefrontal cortex in schizophrenic subjects. Am J Psychiatry. 1999 Oct;156(10):1580-9. Abstract

Bertolino A, Breier A, Callicott JH, Adler C, Mattay VS, Shapiro M, Frank JA, Pickar D, Weinberger DR. The relationship between dorsolateral prefrontal neuronal N-acetylaspartate and evoked release of striatal dopamine in schizophrenia. Neuropsychopharmacology. 2000 Feb;22(2):125-32. Abstract

Bertolino A, Knable MB, Saunders RC, Callicott JH, Kolachana B, Mattay VS, Bachevalier J, Frank JA, Egan M, Weinberger DR. The relationship between dorsolateral prefrontal N-acetylaspartate measures and striatal dopamine activity in schizophrenia. Biol Psychiatry. 1999 Mar 15;45(6):660-7. Abstract

Carr DB, Sesack SR. Projections from the rat prefrontal cortex to the ventral tegmental area: target specificity in the synaptic associations with mesoaccumbens and mesocortical neurons. J Neurosci. 2000 May 15;20(10):3864-73. Abstract

Deutch AY. Prefrontal cortical dopamine systems and the elaboration of functional corticostriatal circuits: implications for schizophrenia and Parkinson's disease. J Neural Transm Gen Sect. 1993;91(2-3):197-221. Review. Abstract

Jaskiw GE, Karoum F, Freed WJ, Phillips I, Kleinman JE, Weinberger DR. Effect of ibotenic acid lesions of the medial prefrontal cortex on amphetamine-induced locomotion and regional brain catecholamine concentrations in the rat. Brain Res. 1990 Nov 26;534(1-2):263-72. Abstract

Jaskiw GE, Weinberger DR, Crawley JN. Microinjection of apomorphine into the prefrontal cortex of the rat reduces dopamine metabolite concentrations in microdialysate from the caudate nucleus. Biol Psychiatry. 1991 Apr 1;29(7):703-6. No abstract available. Abstract

Lipska BK, Weinberger DR. To model a psychiatric disorder in animals: schizophrenia as a reality test. Neuropsychopharmacology. 2000 Sep;23(3):223-39. Review. Abstract

Meyer-Lindenberg A, Miletich RS, Kohn PD, Esposito G, Carson RE, Quarantelli M, Weinberger DR, Berman KF. Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nat Neurosci. 2002 Mar;5(3):267-71. Abstract

Meyer-Lindenberg A, Kohn PD, Kolachana B, Kippenhan S, McInerney-Leo A, Nussbaum R, Weinberger DR, Berman KF. Midbrain dopamine and prefrontal function in humans: interaction and modulation by COMT genotype. Nat Neurosci. 2005 May;8(5):594-6. Epub 2005 Apr 10. Abstract

Pycock CJ, Kerwin RW, Carter CJ. Effect of lesion of cortical dopamine terminals on subcortical dopamine receptors in rats. Nature. 1980 Jul 3;286(5768):74-6. No abstract available. Abstract

Saunders RC, Kolachana BS, Bachevalier J, Weinberger DR. Neonatal lesions of the medial temporal lobe disrupt prefrontal cortical regulation of striatal dopamine. Nature. 1998 May 14;393(6681):169-71. Abstract

Thierry AM, Blanc G, Sobel A, Stinus L, Golwinski J. Dopaminergic terminals in the rat cortex. Science. 1973 Nov 2;182(4111):499-501. No abstract available. Abstract

Weinberger DR, Berman KF, Illowsky BP. Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia. III. A new cohort and evidence for a monoaminergic mechanism. Arch Gen Psychiatry. 1988 Jul;45(7):609-15. Abstract

Winterer G, Weinberger DR. Genes, dopamine and cortical signal-to-noise ratio in schizophrenia. Trends Neurosci. 2004 Nov;27(11):683-90. Review. Abstract

View all comments by Daniel WeinbergerComment by:  Ricardo Ramirez
Submitted 28 February 2006
Posted 28 February 2006

I read the paper by Simpson et al. from Kandel's group with much interest. It seems that the dopamine hypothesis of schizophrenia has many lives and appears and reappears in many forms. This latest reincarnation combines hyperdopaminergia with the neurodevelopmental hypothesis of the disorder. My initial enthusiasm, however, waned upon closer reading of the paper.

It seems that the various conclusions reached are not wholly supported by the results. The prefrontal cognitive deficits of the D2 mice seem to be extremely subtle. It is difficult to infer specific impairments of working memory performance solely from acquisition effects. The D2 mice require more trials to reach criteria, but how do the mice perform once these criteria are met? To be sure, schizophrenia patients present with learning impairments, but their working memory deficits are persistent and ever present. It is interesting that high-order “executive functions” as measured by attentional set-shifting (e.g., intra- and extra-dimensional shifts) are spared in these mice, given that these depend on the rodent medial frontal cortex and are modulated by dopamine as well (Birrell and Brown, 2000; Tunbridge et al., 2004). Thus, contrary to what has been reported, these mice show normal behavioral flexibility. We are thus left with mice whose prefrontal function, at least behaviorally, is relatively intact.

A more pressing issue is the controls that were used for the experiments. The authors did not compare D2 mice (carrying both transgenes) with mice carrying the same two transgenes but who did not at any time express the D2 receptor. Instead the authors compared the D2R expressing mice with their littermates who carried no transgene or either the CamKII or D2 transgenes alone. They state that these groups showed no differences, but their control groups were of nine mice, so there is a potential lack of power to detect any differences between these groups. It will be of interest to know whether any of the other striatal D2 overexpressing lines that were created show similar phenotypes. Lacking this information, we cannot be sure that the subtle effect on behavior is not due to the disruption of another gene by the random insertion of the D2 transgene.

This paper is a natural extension of many years of work showing the balance between cortical and subcortical dopamine systems (Grace, 1991). A brief transient overexpression of striatal D2Rs during development does seem to affect DA function long into adulthood. This mouse model also reflects the long-used strategy of probing those systems thought to underlie the pathophysiology of schizophrenia. These models are of great benefit, but whether they shed any light on the cause or etiology of the disorder is an open question. One would hope that with these now sophisticated genetic tools and the identification of several reliable susceptibility genes (NRG1, DTNBP1, DISC1), more etiologically relevant mouse models can be created.

References:
Birrell JM and Brown VJ. Medial frontal cortex mediates perceptual attentional set shifting in the rat. J Neurosci. 2000 Jun 1;20(11):4320-4. Abstract Grace AA. Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia. Neuroscience. 1991;41(1):1-24. Abstract Tunbridge EM, Bannerman DM, Sharp T, Harrison PJ. Catechol-o-methyltransferase inhibition improves set-shifting performance and elevates stimulated dopamine release in the rat prefrontal cortex. J Neurosci. 2004 Jun 9;24(23):5331-5. Abstract

View all comments by Ricardo RamirezComment by:  Tomiki SumiyoshiPhilip Seeman (Disclosure)
Submitted 7 March 2006
Posted 8 March 2006
  I recommend the Primary Papers

Comment by Tomiki Sumiyoshi and Philip Seeman
Kellendonk et al. report various behavioral and neurochemical findings from transgenic mice expressing an increased number of dopamine (DA)-D2 receptors in the striatum, labeled by 3H-spiperone. These mice showed deficits in some aspects of working memory, a cognitive domain associated with the prefrontal cortex function.

This study was prompted by the landmark hypothesis that DA supersensitivity in some of the subcortical brain regions, such as the striatum, constitutes a neurochemical basis for psychotic symptoms of schizophrenia (e.g., van Rossum, 1966; Seeman et al., 2005). Conventionally, dysregulation of DA-related behaviors, including enhanced locomotor activity and stereotypy, as well as disrupted prepulse inhibition, have been thought to reflect psychosis-related symptoms. However, the D2 receptor transgenic mice did not demonstrate alterations in any of these behavioral measures, although an in vitro assay indicated reduced DA-induced adenylate cyclase activity in these animals. To follow the behavioral changes after challenging the mice with amphetamine or other DA-agonists would have conveyed more information on whether the up-regulated D2 receptors are actually functional.

It is also crucial to determine if there is a shift of D2 receptors to the high-affinity state, or functional state (D2High) (Seeman et al., 2005), in this animal model of schizophrenia. It is argued that D2High sites may be more relevant to psychotic symptoms than the total density of D2 receptors measured by conventional binding methods, such as that used by Kellendonk et al. with 3H-spiperone as a ligand (Seeman et al., 2005; Sumiyoshi et al., 2005). In fact, increased proportions of D2High have been reported in various animal models of psychosis, including those based on the neurodevelopmental hypothesis of schizophrenia (Seeman et al., 2005; Sumiyoshi et al., 2005).

Kellendonk et al. found that the extra D2 receptors in the striatum were associated with the cognitive disturbances. Since it has been found that overexpression of the catechol-O-methyl transferase (COMT) gene also impairs cognitive function (Chen et al., 2005), further research is needed to determine if the cognitive deficits result from overexpression of these specific genes and not just any gene.

References:

van Rossum JM. The significance of dopamine-receptor blockade for the mechanism of action of neuroleptic drugs. Arch Int Pharmacodyn Ther. 1966 Apr;160(2):492-4. No abstract available. Abstract

Seeman P, Weinshenker D, Quirion R, Srivastava LK, Bhardwaj SK, Grandy DK, Premont RT, Sotnikova TD, Boksa P, El-Ghundi M, O'dowd BF, George SR, Perreault ML, Mannisto PT, Robinson S, Palmiter RD, Tallerico T. Dopamine supersensitivity correlates with D2High states, implying many paths to psychosis. Proc Natl Acad Sci U S A. 2005 Mar 1;102(9):3513-8. Epub 2005 Feb 16. Abstract

Sumiyoshi T, Seeman P, Uehara T, Itoh H, Tsunoda M, Kurachi M. Increased proportion of high-affinity dopamine D2 receptors in rats with excitotoxic damage of the entorhinal cortex, an animal model of schizophrenia. Brain Res Mol Brain Res. 2005 Oct 31;140(1-2):116-9. Epub 2005 Jul 28. Abstract

Chen J, Lipska BK, Weinberger DR. New genetic mouse models of schizophrenia: Mimicking cognitive dysfunction by altering susceptibility gene expression. Neuropsychopharmacology. 2005; 30 (Suppl 1):S12-13.

View all comments by Tomiki Sumiyoshi
View all comments by Philip SeemanComment by:  Patricia Estani
Submitted 7 March 2006
Posted 8 March 2006
  I recommend the Primary Papers

I agree with Dr Weinberger's comments about the work of Kellendonk et al. In this sense, the cortical, frontal-striatal connections are well-known circuits involved in the development of schizophrenia.

Dr. Weinberger, in 1992, reported studies from limbic-prefrontal circuits, connections involved in schizophrenia pathophysiology (Weinberger et al., 1992). This work used an inverse experimental methodology (of corroborating the existing relationship between frontal cortex and the striatum) from the methodology commonly used (search for the line-activation in frontal cortex, then see the results in the striatum).

The most outstanding part of the study is one dedicated to the developmental approach. Thus, in the article, it was clear that restoring the normal DA function in the striatum did not restore cognitive functioning. As this article demonstrates, developmental approaches are excellent for the understanding of the neurobiology of schizophrenia.

References:

Weinberger DR, Berman KF, Suddath R, Torrey EF. Evidence of dysfunction of a prefrontal-limbic network in schizophrenia: a magnetic resonance imaging and regional cerebral blood flow study of discordant monozygotic twins. Am J Psychiatry. 1992 Jul;149(7):890-7. Abstract

View all comments by Patricia Estani

Comments on Related News


Related News: Priming the LTP Pump—Dopamine Delivers in Prefrontal Cortex

Comment by:  Andreas Meyer-Lindenberg
Submitted 15 May 2006
Posted 15 May 2006
  I recommend the Primary Papers

I think this is an interesting paper, as it shows that alterations in tonic dopaminergic stimulation can result in a pronounced and qualitative switch (LTD to LTP) in the behavior of prefrontal neurons. Although the concept of tonic versus phasic dopaminergic stimulation has been adopted widely by the schizophrenia research community, the majority of the preclinical work has focused on acute changes in dopamine concentration and on subcortical structures, especially the nucleus accumbens, and from my perspective as a clinical researcher, it is welcome to see some data that extend to prefrontal cortex and longer timescales, although it must be emphasized that this paper concerns results from rats, in slices in vitro, using tetanic stimulation, and that the pretreatment with dopamine lasted for 40 minutes only. With these caveats, it is exciting to see that pretreatment with dopamine after what the authors presume is a 4-hour period of neurotransmitter depletion during slice preparation produces LTP after a weak tetanic stimulus, compared to LTD that the same stimulus evoked without dopamine priming. Since LTD arose under conditions of relative dopamine depletion, which might reflect, at least in directionality, the situation in schizophrenia, these data suggest that functionally impairing qualitative changes in a neuronal response in prefrontal cortex of relevance for working memory function could result from quantitative reductions in extracellular (tonic) dopamine content. It is also of interest that the authors demonstrate that the LTP requires concurrent stimulation of metabotropic glutamate receptors, suggesting a mechanism by which widely studied risk genes for schizophrenia such as COMT and GRM3 could interact in impairing prefrontal cortex function.

View all comments by Andreas Meyer-Lindenberg

Related News: Priming the LTP Pump—Dopamine Delivers in Prefrontal Cortex

Comment by:  Patricia Estani
Submitted 3 June 2006
Posted 3 June 2006
  I recommend the Primary Papers

Related News: Priming the LTP Pump—Dopamine Delivers in Prefrontal Cortex

Comment by:  Terry Goldberg
Submitted 20 June 2006
Posted 20 June 2006

Matsuda et al. demonstrate that priming D1 and D2 receptors may induce LTP; otherwise, LTD develops. To elaborate, a weak tetanic stimulation and dopamine stimulation produces LTD. However, if dopamine is perfused for 12 to 40 minutes at D1 and D2 receptors and a tetanic stimulus is provided, LTP, a form of cellular learning associated with memory, develops. This study has potentially important implications for understanding the cause of prefrontally based failures in information processing in schizophrenia. It gives additional weight to arguments that reduced dopaminergic tone at the cortical level is responsible for at least some of the cognitive problems associated with the disorder.

It also helps make sense out of some otherwise anomalous data in the literature. For instance, in manipulations of several tests of purported attentional control and vigilance problems, findings appeared more consistent with difficulties in constructing a representation than with attention per se in target detection (e.g., Elvevag et al., 2000; Fuller et al., 2005).

One thing that I would certainly give an eyetooth to know is how the authors view their work in light of findings by Seamans and Goldman-Rakic on differences in the consequences of stimulation of D1 and D2 receptors (simplistically, that D1 activation promotes task-relevant information, while D2 stimulation may produce task-irrelevant information processing experienced as interference).

Caveat Emptor: I don’t have the expertise to comment on the slice preparation methodology.

References:

Elvevag B, Weinberger DR, Suter JC, Goldberg TE. Continuous performance test and schizophrenia: a test of stimulus response compatibility, working memory, response readiness, or none of the above? Am J Psychioatry 2000; 157:772-780. Abstract

Fuller RL, Luck SJ, McMahon RP, Gold JM. Working memory consolidation is abnormally slow in schizophrenia. J Abnorm Psychol 2005; 114:279-290. Abstract

View all comments by Terry Goldberg

Related News: Priming the LTP Pump—Dopamine Delivers in Prefrontal Cortex

Comment by:  Satoru Otani
Submitted 22 July 2006
Posted 24 July 2006

In his June 20 comment, Dr. Goldberg raised an important question concerning our paper: how our results, showing the necessity of D1+D2 receptor coactivation for prefrontal LTP induction and priming, fit into the scheme proposed by Seamans et al., 2001, that is, the differential roles played by D1 and D2 receptors for prefrontal cortex (PFC) cognitive processes.

I think I have to first point out that the dependency of PFC long-term potentiation (LTP) induction (let alone "priming" now) on DA receptor subtypes may vary among subpopulations of PFC synapses. In ventral hippocampus (HC)-PFC synapses, LTP induction requires D1 but not D2 receptors (Gurden et al., 2000). This in vivo study fits with the idea that HC-PFC projection and its D1 receptor-mediated modulation are critical in spatial information processing (working memory) and encoding of this information. However, recent in vivo results of Yukiori Goto at the University of Pittsburgh (personal communication, but see Goto and Grace, 2005) indicate that LTP induction in cortico-cortical synapses in the PFC may be dependent on both D1 and D2 receptors, similar to our case. Dr. Goto found that while synaptic potentiation in the HC-PFC synapses indeed depends only on D1 receptors, potentiation in cortico-cortical synapses, stimulated by the electrode inserted in the superficial layer of the PFC as in our preparation, depends on the activation of both D1 and D2 receptors. Thus, it appears that DA receptor dependency of LTP induction differs between the HC projection input and the cortico-cortical input—the former dependent only on D1 receptors and the latter on D1+D2 receptors.

How significant this difference might be functionally is, of course, still an issue for speculation. It seems clear that working memory input from the HC (and strengthening of this input), which may depend only on D1 receptors, are critical for PFC cognitive function. But also, other cortical inputs, which are not necessarily related to the attention-driven working memory, may be as critical for the formation and achievement of goal-directed behavior, and strengthening of these cortical inputs may depend on D1+D2 receptors. Incidentally, Dr Goto also showed that the organization of a planned behavior tested in a modified radial-arm maze task requires not only intact HC-PFC connection but also the activation of both D1 and D2 receptors within the PFC (Goto and Grace, 2005). We are tempted to suggest that neuronal traces within the PFC necessary for the generation of goal-directed behavior may be heterogeneous both in their input origin and in their formation mechanism.

References:

Seamans JK, Gorelova N, Durstewitz D, Yang CR (2001) Bidirectional dopamine modulation of GABAergic inhibition in prefrontal cortical pyramidal neurons. J Neurosci 21, 3628-3638. Abstract

Gurden H, Takita M, Jay TM. Essential role of D1 but not D2receptors in the NMDA receptor-dependent long-term potentiation at hippocampal-prefrontal cortex synapses in vivo. J Neurosci. 2000 Nov 15;20(22):RC106. Abstract

Goto Y, Grace AA (2005) Retrospective and prospective memory processing in the hippocampal—prefrontal cortical network. Soc Neurosci Abstr 413.3.

View all comments by Satoru Otani

Related News: Priming the LTP Pump—Dopamine Delivers in Prefrontal Cortex

Comment by:  Jeremy Seamans
Submitted 26 July 2006
Posted 27 July 2006

Drs. Goldberg and Otani raise some excellent points in their comments on the Matsuda et al. paper. As Dr. Otani alluded to in his latest comment, it is useful to define exactly what is being modulated under different experimental conditions and how this all relates to prefrontal cortex (PFC) function in general.

Dr Otani’s studies investigate synaptic plasticity induced by tetanic stimulation and how this process is modulated by tonic dopamine (DA). Long-term potentiation/long-term depression (LTP/LTD) induced by tetanic stimulation has provided us with perhaps the best model of the cellular basis of long-term memory and has been proposed to underlie, among other things, various aspects of long-term spatial memory and declarative memory. LTP is a long-lasting, passive, associational memory mechanism, unlike working memory that is transient in nature, relies on active processing and is not associational. Therefore, in PFC, it would be highly unlikely that LTP/LTD is the neural mechanism of working memory. However, to solve a working memory problem, one must manipulate newly acquired information within a certain context or based on a pre-learned rule. Perhaps the best example of how these processes relate can be found in White and Wise, 1999, and Wallis et al., 2001, who investigated the activation of PFC neurons in situations where two different abstract rules could be applied. PFC neurons showed different degrees of activation during a delay period depending on the preference of the neuron for a specific task rule. Therefore, stable long-standing rules regulate how strongly a cell in PFC exhibits short-term memory related activity. These rules were learned over time and were stable. LTP/LTD are as good mechanisms as any for their cellular basis. This implies that LTP/LTD-like mechanisms influenced the manner in which PFC neurons exhibited transient working memory related activity. Therefore, as shown by Matsuda et al. and suggested by others (e.g., Lisman and Grace, 2005), a long-term memory mechanism, perhaps involved in the formation of stable rules, is subjected to modulation by tonic and phasic DA. This long-term memory in turn regulates the online active processing of information in working memory.

In contrast, many investigators have proposed that DA is also able to directly modulate working memory related activity. As noted by Dr. Goldberg, in addition, we have suggested that the mode of modulation is different for D1 and D2 receptors in PFC. Like task rules, DA appears to modify the strength of delay-period activity (e.g., Sawaguchi, 2001). Furthermore, the modulation of synaptic currents by DA, especially via D1 receptors, is very long-lasting and has been termed “late potentiation” and in fact shares aspects of the late phase of LTP (Huang and Kandel, 1995). However, unlike stable task rules, DA levels can change quickly and dynamically, and as a result, delay-period activity may be increased or decreased depending on the level of DA and the differential activation of D1 and D2 receptors, even if the same task rule is being implemented. The dynamic modulation of DA levels depends on a variety of factors such as intrinsic motivation, stress, and even the strength of the active memory trace (Phillips et al., 2004).

Therefore, DA modulates LTP/LTD, which in turn may be involved in the rule-dependent modification of delay-period activity. DA can also directly modulate the ionic currents involved in actually generating delay-period activity. Although this modulation can be long-lasting, DA levels and activation of different DA receptors change dynamically and the mode of modulation could continuously vary based on a variety of intrinsic and task-dependent variables.

Perhaps one implication of all this for schizophrenia would be that dysfunction of DA-dependent modulation of LTP/LTD would lead to an inability to accurately store or implement the appropriate rule for a given situation. In contrast, dysfunction of the direct DA modulation of ionic and synaptic currents could lead to more immediate issues such as distractability or pathologically focused processing of information within working memory (Seamans et al., 2001; Seamans and Yang, 2004).

References:

Huang YY, Kandel ER. D1/D5 receptor agonists induce a protein synthesis-dependent late potentiation in the CA1 region of the hippocampus. Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):2446-50. Abstract

Lisman JE, Grace AA. The hippocampal-VTA loop: controlling the entry of information into long-term memory. Neuron. 2005 Jun 2;46(5):703-13. Review. Abstract

Phillips AG, Ahn S, Floresco SB. Magnitude of dopamine release in medial prefrontal cortex predicts accuracy of memory on a delayed response task. J Neurosci. 2004 Jan 14;24(2):547-53. Abstract

Sawaguchi T. The effects of dopamine and its antagonists on directional delay-period activity of prefrontal neurons in monkeys during an oculomotor delayed-response task. Neurosci Res. 2001 Oct;41(2):115-28. Abstract

Seamans JK, Gorelova N, Durstewitz D, Yang CR. Bidirectional dopamine modulation of GABAergic inhibition in prefrontal cortical pyramidal neurons. J Neurosci. 2001 May 15;21(10):3628-38. Abstract

Seamans JK, Yang CR. The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Prog Neurobiol. 2004 Sep;74(1):1-58. Review. Erratum in: Prog Neurobiol. 2004 Dec;74(5):321. Abstract

Wallis JD, Anderson KC, Miller EK. Single neurons in prefrontal cortex encode abstract rules. Nature. 2001 Jun 21;411(6840):953-6. Abstract

White IM, Wise SP. Rule-dependent neuronal activity in the prefrontal cortex. Exp Brain Res. 1999 Jun;126(3):315-35. Abstract

View all comments by Jeremy Seamans

Related News: Studies Suggest Potential Roles for Dysbindin in Schizophrenia

Comment by:  Philip Seeman (Disclosure)
Submitted 29 November 2007
Posted 29 November 2007
  I recommend the Primary Papers

The publication by Iizuka and colleagues is an important advance toward unraveling the basic biology of psychosis in general, and schizophrenia in particular. This is because they have found that a pathway known to be genetically associated with schizophrenia can alter the surface expression of dopamine D2 receptors. D2 continues to be the main target for all antipsychotic drugs (including aripiprazole and even the new Lilly glutamate agonists that have a potent affinity for D2High receptors).

In fact, the authors of this excellent study may do well to go one step further by testing whether the downregulation of dysbindin actually increases the proportion of D2 receptors that are in the high-affinity state, namely D2High. This is because all schizophrenia animal models markedly increase the proportion of D2High receptors by 100 to 900 percent (Seeman et al., 2005; Seeman et al., 2006). This generalization holds for animal models based on brain lesions, sensitization by amphetamine, phencyclidine, cocaine, caffeine or corticosterone, birth injury, social isolation, and more than 15 gene deletions in pathways for glutamate (NMDA), dopamine, GABA, acetylcholine, and norepinephrine. Although the proportion of D2High receptors invariably increases markedly, the total number of D2 receptors is generally unchanged, slightly reduced, or modestly elevated.

This publication for the first time bridges the hitherto wide gap between genetics and the antipsychotic targeting of the main cause of psychotic signs and symptoms, which is excessive D2 activity, presumably that of D2High, the functional component of D2.

References:

Seeman P, Weinshenker D, Quirion R, Srivastava LK, Bhardwaj SK, Grandy DK, Premont RT, Sotnikova TD, Boksa P, El-Ghundi M, O'dowd BF, George SR, Perreault ML, Männistö PT, Robinson S, Palmiter RD, Tallerico T. Dopamine supersensitivity correlates with D2High states, implying many paths to psychosis. Proc Natl Acad Sci U S A. 2005 Mar 1;102(9):3513-8. Epub 2005 Feb 16. Abstract

Seeman P, Schwarz J, Chen JF, Szechtman H, Perreault M, McKnight GS, Roder JC, Quirion R, Boksa P, Srivastava LK, Yanai K, Weinshenker D, Sumiyoshi T. Psychosis pathways converge via D2high dopamine receptors. Synapse. 2006 Sep 15;60(4):319-46. Review. Abstract

View all comments by Philip Seeman

Related News: Studies Suggest Potential Roles for Dysbindin in Schizophrenia

Comment by:  Christoph Kellendonk
Submitted 4 December 2007
Posted 4 December 2007

The study by Iizuka and colleagues is indeed very interesting. It suggests that one of the most promising risk genes for schizophrenia, the dysbindin gene, may functionally interact with dopamine D2 receptors. The D2 receptor itself is an old candidate in the study of schizophrenia, mostly because until very recently all antipsychotic medication had been directed against D2 receptors. But in addition, PET imaging studies have shown that the density and occupancy of D2 receptors is increased in drug-free and drug-naïve patients with schizophrenia.

How could this increase arise? In a subpopulation of patients it may be due to a polymorphism in the D2 receptor gene, the C957T polymorphism. The C-allele increases mRNA stability and has been found to be associated with schizophrenia, though obviously not all patients carry the C-allele. Iizuka and colleagues found an independent way in which the genetic risk factor dysbindin may upregulate D2 receptor signaling. Because dysbindin is downregulated in the brains of patients with schizophrenia, they used siRNA technology to study the molecular consequences of decreased dysbindin levels in cell culture.

They found that downregulation of dysbindin increases D2 receptor density in the outer cell membrane, suppresses dopamine-induced D2 receptor internalization, and increases D2 receptor signaling. The study is very promising but requires further confirmation.

How specific are the observed effects for D2 receptors? Because dysbindin is involved in both membrane trafficking and degradation of synaptic vesicles, knocking down dysbindin in growing cells may affect many physiological processes, one of them being D2 receptor signaling. Does quinpirole treatment differentially affect GTPgS incorporation in siRNA and control cells? This would be a more immediate way of looking at D2 signaling than measuring CREB phosphorylation. And, of course, the most important question is, What will happen in vivo? Maybe the sandy mouse, which carries a deletion in the dysbindin gene, could be of help here. Using these mice for a similar line of experiments may answer this question.

Iizuka and colleagues found an exciting new functional interaction between two major molecules involved in schizophrenia. I believe that these are the kind of interactions we have to look for if we want to understand complex genetic disorders such as schizophrenia.

View all comments by Christoph Kellendonk

Related News: Cognition and Dopamine—D1 Receptors a Damper on Working Memory?

Comment by:  Michael J. Frank
Submitted 19 February 2009
Posted 19 February 2009

McNab and colleagues provide groundbreaking evidence showing that cognitive training with working memory tasks over a five-week period impacts D1 dopamine receptor availability in prefrontal cortex. Links between prefrontal D1 receptor function and working memory are often thought to be one-directional, i.e., that better D1 function supports better working memory, but here the authors show that working memory practice reciprocally affects D1 receptors.

An influential body of empirical and theoretical research suggests that an optimal level of prefrontal D1 receptor stimulation is required for working memory function (e.g., Seemans and Yang, 2004). Because acute pharmacological targeting of prefrontal D1 receptors reliably alters working memory, causal directionality from D1 to working memory remains evident. Nevertheless, these findings cast several other studies in a new light. Namely, when a population exhibits impaired (or enhanced) working memory and PET studies indicate differences in dopaminergic function, it is no longer clear which variable is the main driving factor. For example, those who engage in cognitively demanding tasks on a day-to-day basis may show better working memory and dopaminergic correlates may be reactive rather than causal. Finally, the possibility cannot be completely discounted that the observed changes in D1 receptor binding may reflect a learned increase in prefrontal dopamine release; this would explain the general tendency for D1 receptor availability to decrease with cognitive training, due to competition with endogenous dopamine.

The McNab study also finds that only cortical D1 receptors, and not subcortical D2 receptors, were altered by cognitive training. The significance of this null effect of D2 receptors is not yet clear. First, all tasks used in the training study involved recalling the ordering of a sequence of stimuli and repeating them back when probed. While clearly taxing working memory, these tasks did not require subjects to attend to some stimuli while ignoring other distracting stimuli, and did not require working memory manipulation. Both manipulation and updating are characteristics of many working memory tasks, particularly those that depend on and/or activate the basal ganglia. Indeed, previous work by the same group (McNab and Klingberg, 2008) showed that basal ganglia activity is predictive of the ability to filter out irrelevant information from working memory. Similarly, Dahlin et al. (2008) reported that training on tasks involving working memory updating leads to generalized enhanced performance in other working memory tasks, and that this transfer of learned knowledge is predicted by striatal activity. These results are consistent with computational models suggesting that the basal ganglia act as a gate to determine when and when not to update prefrontal working memory representations and are highly plastic as a function of reinforcement. Thus, future research is needed to test whether training on filtering, updating, or manipulation tasks leads to changes in striatal D2 receptor function.

References:

McNab, F. and Klingberg, T. (2008). Prefrontal cortex and basal ganglia control access to working memory. Nature Neuroscience, 11, 103-107. Abstract

Dahlin, E., Neely, A.S., Larsson, A., Bäckman, L. & Nyberg, L. (2008). Transfer of learning after updating training mediated by the striatum. Science, 320, 1510-1512. Abstract

Seamans, J.K. and Yang, C.R. (2004). The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Progress in Neurobiology, 74, 1-57. Abstract

View all comments by Michael J. Frank

Related News: Cognition and Dopamine—D1 Receptors a Damper on Working Memory?

Comment by:  Terry Goldberg
Submitted 3 March 2009
Posted 3 March 2009

This is an important article that describes profound changes in the dopamine D1 receptor binding potential after working memory training in healthy male controls. The study rests on prior work that has demonstrated changes in brain volume with practice (e.g., Draganski and May, 2008), and dopamine can be released at the synapse in measurable amounts even during, dare I say, fairly trivial activities (e.g., playing a video game (Koepp et al., 1998). The present study demonstrated that binding potential of D1 receptors decreased in cortical regions (right ventrolateral frontal, right dorsolateral PFC, and posterior cortices) with training, and the magnitude of this decrease correlated with the improvement during training. Binding potential of D2 receptors in the striatum did not change. Unfortunately, D2 receptors in the cortex could not be measured with raclopride.

Two points come to mind. One is theoretical—how long would such a change remain, i.e., is it transient or is it fixed? This has implications for understanding practice-related phenomena and their transfer or consolidation. The second is technical. A number of studies have shown that practice can change not only the magnitude of a physiologic response, but also its location (see Kelly and Garavan for a review, 2005). Thus, the circuitry involved in learning a task may be different than the circuitry involved in implementing a task after it is well learned. By constraining areas to those activated in fMRI during initial working memory engagement, it is possible that other critical areas were not monitored for binding potential changes.

References:

Draganski B, May A. Training-induced structural changes in the adult human brain. Behav Brain Res . 2008 Sep 1 ; 192(1):137-42. Abstract

Kelly AM, Garavan H. Human functional neuroimaging of brain changes associated with practice. Cereb Cortex . 2005 Aug 1 ; 15(8):1089-102. Abstract

Koepp MJ, Gunn RN, Lawrence AD, Cunningham VJ, Dagher A, Jones T, Brooks DJ, Bench CJ, Grasby PM. Evidence for striatal dopamine release during a video game. Nature . 1998 May 21 ; 393(6682):266-8. Abstract

View all comments by Terry Goldberg

Related News: SfN 2013—Different Roads to Dopamine Dysfunction in Schizophrenia

Comment by:  Melkaye Melka
Submitted 5 December 2013
Posted 9 December 2013

Atypical antipsychotics have been used to treat psychiatric disorders such as schizophrenia. However, the mechanisms of action of antipsychotics remain poorly understood. On the other hand, dopamine neurons form the focus of attention in the etiology and pathophysiology of schizophrenia. As noted by Michele Solis’ snapshot from the conference, the work of Grace and colleagues showed that prenatal injections of methylazoxymethanol acetate (MAM), a DNA-methylating agent, lead to hyperactive dopamine signaling (Moore et al., 2006). Focusing on the mechanisms of action, previous studies have suggested that antipsychotic drugs may cause promoter methylation of genes involved in psychosis (Dong et al., 2009). DNA methylation changes have also been associated with major psychosis (Mill et al., 2008).

In a recent in-vivo study, we have observed organ-specific (hippocampus, cerebellum, and liver) changes in DNA methylation following a therapeutic dose of a model antipsychotic drug (olanzapine) (Melka et al., 2013, in press). In particular, we noted that the dopamine signaling pathway was one of the most significant networks affected by olanzapine-induced DNA methylation changes. Specifically, the results showed that olanzapine significantly alters promoter DNA methylation of genes involved in dopamine synthesis, transport, receptors, and metabolism. These results support a dopamine hypothesis of psychosis and a role for epigenetic mechanisms in the development of psychosis, as well as its treatment with antipsychotic drugs. Given that some of the genes affected are tissue specific and affect a variety of networks, our results could also explain the delayed therapeutic response of antipsychotics as well as their patient-specific efficacy and side effects.

References:

Dong E, Grayson DR, Guidotti A, Costa E. Antipsychotic subtypes can be characterized by differences in their ability to modify GABAergic promoter methylation: Epigenomics 2009; 1: 201-1. Abstract

Melka MG, Castellani CA, Laufer BI, Rajakumar N, O’Reilly R and Singh SM. Olanzapine induced DNA methylation changes support the dopamine hypothesis of psychosis. J Mol Psychiatry; 2013; 1:19. (In press)

Mill J, Tang T, Kaminsky Z, Khare T, Yazdanpanah S, Bouchard L, Jia P, Assadzadeh A, Flanagan J, Schumacher A, Wang SC, Petronis A. Epigenomic profiling reveals DNA-methylation changes associated with major psychosis. Am J Hum Genet . 2008 Mar ; 82(3):696-711. Abstract

Moore H, Jentsch JD, Ghajarnia M, Geyer MA, Grace AA. A neurobehavioral systems analysis of adult rats exposed to methylazoxymethanol acetate on E17: implications for the neuropathology of schizophrenia. Biol Psychiatry . 2006 Aug 1 ; 60(3):253-64. Abstract

View all comments by Melkaye Melka