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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.

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...  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...  Read more

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...  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...  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...  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...  Read more

View all comments by Patricia Estani
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