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.