Model for madness: engineered mice have schizophrenia-like symptoms.

Scientists have genetically altered mice so that they mimic the deficits in short-term memory and attention of schizophrenic patients. The new animal model could shed light on the causes and treatment of these symptoms, which respond only minimally to current drugs.

Memory and attention problems are only part of schizophrenia, a complex disorder that also includes hallucinations, delusions, and social isolation. Scientists suspect that many of schizophrenia's symptoms stem from hyperactivity in the brain's machinery for using the signal transmitter dopamine.

Previous research had shown that schizophrenics have slightly more of a particular dopamine receptor, known as the D2 receptor, on nerve cells within a central part of the brain called the striatum. Scientists weren't sure whether this increase in D2 receptors was a cause of schizophrenic symptoms or a result of drugs used to treat the disorder, notes Eleanor Simpson, a neuroscientist at Columbia University.

Rather than study schizophrenia by crafting mice that have all the characteristics of the disease, she and her colleagues, led by Columbia's Eric Kandel, decided to make mice that simply had more D2 receptors in their striata than normal. "We said, 'Let's ... see what aspects of the disorder happen with that change"" Simpson says.

Kandel's team genetically engineered mice to have about a 15 percent excess of D2 receptors in their striata. A wrinkle in the genetic strategy also gave the researchers the option of shutting off the extra receptors by feeding the animals an antibiotic called doxycycline.

The engineered mice behaved much as normal ones did in tests of general cognition, such as learning the location of a platform hidden under water. However, the researchers noticed some differences when they tested the animals working memory--a type of short-term memory held only during a task and briefly afterward.

By using working memory, normal mice quickly learned that researchers were alternating in which side of a T-shaped maze they hid food. In contrast, the engineered mice floundered at the test, taking significantly more trials to master the game.

An aspect of attention also diminished in the engineered mice. When the researchers hid a treat under one of two piles of bedding with different scents and then switched the scent hiding the treat, normal mice quickly learned which pile would yield the reward. The engineered mice dug in the original pile for significantly longer before trying the other one.

When researchers shut off the extra D2 receptors by feeding engineered mice doxycycline, they found no change in these animals' memory and attention deficits. The finding suggests that extra D2 receptors cause permanent brain damage, Kandel says.

That damage probably occurs while the brain is still developing and might be permanent, says Kandel. If so, he adds, it could explain why antipsychotic drugs that target D2 receptors don't improve schizophrenic patients' cognitive deficits.

The mouse findings, reported in the Feb. 16 Neuron, could help researchers develop new drugs to prevent such early brain damage from occurring in people who may be susceptible to schizophrenia, says neuroscientist Solomon Snyder of Johns Hopkins Medical Institutions in Baltimore.