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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...  Read more


View all comments by Barbara K. Lipska

Comment 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. Glatt


Comment 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...  Read more


View all comments by Daniel Weinberger

Comment 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...  Read more


View all comments by Ricardo Ramirez

Comment 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...  Read more


View all comments by Tomiki Sumiyoshi
View all comments by Philip Seeman

Comment 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

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