Disrupted brain chatter produces schizophrenia-like symptoms in mice

Shushing neural chitchat in mouse brains can spark schizophrenia-like symptoms, a new study suggests. The findings are the first to demonstrate — at least in mice — that curbing communication among neurons in certain parts of the brain can cause some of the cognitive problems associated with schizophrenia.

By muzzling neurons in the mediodorsal thalamus, or MD — a cell cluster that sends signals to the brain’s outer layer — researchers hindered mouse memory and learning in much the same way that schizophrenia seems to do in humans, scientists report March 20 in Neuron.

Cognitive problems in schizophrenia have long been a mystery to scientists and a troubling symptom for people with the condition. The findings suggest that the problems stem from the thalamus, says neuropsychologist Neil Woodward of Vanderbilt University in Nashville, who was not involved with the new work.

People with schizophrenia suffer from a range of debilitating symptoms: hallucinations, delusions and social disorders, says study coauthor Christoph Kellendonk of Columbia University. Patients also have problems with short-term memory and learning. Unlike other symptoms, these cognitive problems have been nearly impossible to treat.

Brain imaging of people with schizophrenia had previously linked cognitive defects to changes in the MD — part of a walnut-sized chunk of gray matter snuggled above the brain stem. Normally, the MD relays information to and from the prefrontal cortex, the brain region behind the forehead that controls complex thought. In people with schizophrenia, the imaging showed, the MD is unusually quiet.

Researchers didn’t know if silent MDs triggered schizophrenia symptoms or were by-products of the disease and its treatment, says study coauthor Joshua Gordon of Columbia University. To find out, he, Kellendonk and colleagues silenced mouse MDs and then tested the animals’ thinking skills.

The researchers pumped a virus through a fine needle into the MD, which is smaller than a ball-point pen tip. With the addition of a specific drug, the virus makes MD cells churn out a protein that hushes neurons.

The method dialed back chatter in about 30 to 40 percent of MD neurons, and in each of those neurons it turned down communication by 30 percent. Even this slight lull in neural conversation was enough to fog mice’s thinking.

The team ran the mice through two tests of learning and memory. In the first test, researchers taught mice that they would receive a tasty drop of milk if they pressed a lever when a steady light turned on. Then the researchers changed the rules. Now to get the treat, the mice had to press the lever when the light flashed.

Next, the team tested the animals’ memory in a T-shaped maze: The mice had to remember which arm to explore to find food.

In both tasks, mice without talkative MDs had trouble figuring out how to collect their reward. They took longer than normal mice to learn the new light rules and to find food in the maze.

When researchers recorded neural activity in the MD and the prefrontal cortex they found that disrupting MD function also threw off prefrontal cortex activity.

The results suggest that stifling MD communication with the prefrontal cortex could explain cognitive problems in people with schizophrenia, Gordon says. By learning more about this communication, he says, “perhaps we could design treatments that restore cognitive function.”