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Engineered mouse mimics cognitive aspects of schizophrenia

Researchers have developed a mouse strain in which the abnormal activity of the dopamine machinery in a specific part of the brain causes cognitive and behavioral impairments mimicking those in human schizophrenics.

The achievement is important, because creating an animal model of any schizophrenic characteristics has not been done before. And schizophrenia's genetic and physiological complexities have seriously hindered efforts to understand the disorder.

Dr.s Christoph Kellendonk, Eleanor H. Simpson, Eric R. Kandel and colleagues reported their development of the mouse model in an article in the February 16, 2006, issue of Neuron.

In a preview of the study in the same issue of Neuron, neuroscientist Solomon Snyder wrote that the researchers' findings--along with studies implicating specific genes in schizophrenia--"afford a basis for optimism" that the engineered mice could provide an animal model for schizophrenia. "In this case, the transgenic mice developed by Kellendonk and colleagues may provide a valuable tool for understanding this most malignant of mental disorders," wrote Snyder.

Kellendonk and his colleagues based their experiments on a widely accepted theory that hyperactivity in the brain's dopamine machinery plays a central role in schizophrenia. Dopamine is a major neurotransmitter in the brain--a chemical messenger that one neuron launches at its neighbor to trigger a nerve impulse in the receiving neuron.

The major antipsychotic drugs are believed to "dial down" the dopamine machinery by blocking receptors for dopamine on the surface of neurons. Also, amphetamines, which release dopamine, are known to aggravate schizophrenic symptoms.

The researchers also based their experiments on evidence that abnormalities in the brain region known as the striatum can affect cognitive function in schizophrenics--by indirectly influencing the prefrontal cortex, a major center for cognitive function.

To mimic the hyperactive dopamine machinery, the researchers created a genetically altered mouse strain in which dopamine receptors were overexpressed only in the striatum. What's more, they engineered the mouse strain so that they could shut down this overexpression by giving the mice the antibiotic doxycycline.

The researchers found that the engineered animals showed no difference from normal mice in their general cognitive functioning, activity level, sensorimotor functioning, or anxiety.

However, the mice did show the same kinds of specific cognitive deficits seen in human schizophrenics. In tests using mazes, the animals showed deficits in "working memory"--the temporary storage of information required for a task. The animals also showed poorer behavioral flexibility; they were less able than normal mice to reverse their association of a particular odor with a reward.

Biochemical analyses of the animals' brains revealed that the excess dopamine receptor activity in the striatum contributed to abnormal prefrontal cortical function.

Importantly, found the researchers, they could not reverse these cognitive deficits by using the antibiotic to damp down the dopamine machinery. This finding suggests that the effect of the abnormal dopamine machinery was developmental, they said.

"If increased activation of [dopamine] receptors indeed contributes to the cognitive deficits of patients with schizophrenia, our data could explain why antipsychotics do not greatly ameliorate cognitive deficits," wrote the researchers. "The physiological alterations that are responsible for cognitive deficits may be present long before the first psychotic episode, when treatment usually commences. Thus, treatment with typical antipsychotics may be too late to reverse the physiological alterations that are responsible for the cognitive deficits."

The researchers cautioned that "Rodent models of schizophrenia have significant limitations. The neuronal circuits affected in people are more complex than the analogous circuits in rodents. In particular, the relative size of the prefrontal cortex that is involved in the cognitive deficits is much smaller in rodents than in primates. Some of the cognitive symptoms such as hallucinations or delusions are impossible to address.

"However, rodent models have the advantage of allowing direct tests of cause-effect relationships for specific aspects of the disease, such as some of the cognitive deficits," they concluded. "We here have been able to introduce genetically a single molecular alteration in a restricted and regulated fashion and to study its behavioral and physiological consequences."

The researchers said that their findings suggest that cognitive symptoms of schizophrenia may arise from subtle genetic differences in the dopamine receptor gene in schizophrenics that increase receptor activity.


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Source:Cell Press


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