Building a Better Schizophrenic Mouse

Risk and reward. “Jumping genes” (in green neuron) may help ensure that every brain is unique, but could also contribute to neurological disorders such as schizophrenia.

Risk and reward. "Jumping genes" (in green neuron) may help ensure that every brain is unique, but could also contribute to neurological disorders such as schizophrenia.

Carol Marchetto (Salk Institute) and Alysson Muotri (UCSD)

Hallucinations and paranoia aren't the only symptoms that make life difficult for people with schizophrenia. Problems with memory and other cognitive functions also interfere with daily tasks, such as remembering the way to the office or balancing a checkbook. Now, by dampening the activity of a small group of neurons deep within the mouse brain, researchers have produced cognitive deficits similar to those found in those with schizophrenia, a discovery that they say could potentially lead to new treatments for the disorder, which affects roughly 24 million people worldwide.

There's an ongoing debate over how much mice can mirror human psychiatric diseases, ranging from autism to depression. Still, neuroscientists often turn to rodents to study specific features of these human conditions. One abnormality that researchers have observed in functional magnetic resonance imaging scans of the brains of people with schizophrenia is an unusually low level of activity from a specific group of neurons near the brain stem. Called the mediodorsal thalamus (MD), the region appears to work with the prefrontal cortex—an area associated with planning and decision-making—to carry out tasks that require us to remember and process multiple pieces of information at once. (Going to the kitchen to fetch something, while remembering what it was you needed, for example.)

In the past, scientists have studied the effects of low brain activity in the MD by cutting it out in mice—an extreme measure that didn't accurately mimic the "mild" reduction in activity seen in schizophrenia, says Columbia University psychiatrist Joshua Gordon. To create a more realistic mouse model of low MD activity, the team devised a new method that uses a virus to embed into the surface of MD neurons receptors that block cellular activity in the presence of a compound called clozapine-N-oxide. The beauty of this approach is its "exquisite specificity," Gordon says—it targets only neurons in the MD, and you can control how many neurons get shut down.

After using clozapine-N-oxide to reduce MD activity in the mice by 30% to 40%, the team ran them through a series of tasks designed to assess cognitive skills that are often affected in schizophrenia. The impaired mice performed badly, Gordon and his co-authors report in today's issue of Neuron. In one test for working memory—the ability to use recent experience to make decisions—the mice were trained to find food in one arm of a maze based on a visual cue. Both the impaired and control mice performed well on the first part of the task. After 7 days, however, the researchers switched the rules: To find food, mice now had to go in the opposite direction of the cue. While the control mice picked up on the new rules in 4 to 5 days, the impaired mice took at least twice as long to learn the task.

Do these mouse memory problems truly mimic those afflicting people with schizophrenia? More research is needed to answer that question, says neurobiologist Christoph Kellendonk of Columbia University, the lead author of the study. However, he says the findings do suggest that drugs that increase the MD's activity could potentially help with some of schizophrenia's most debilitating symptoms.

Although it isn't possible to make true mouse models of schizophrenia, the study is "elegant" and an "important new building block" toward a better understanding of the MD's role in schizophrenia's cognitive deficits, says psychiatrist John Krystal of Yale University.

*Correction, 22 March: A previous version of this article stated that the researchers administered a drug called clozapine to the mice. In fact, they administered a compound called clozapine-N-oxide.

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