Mutations in the gene for calcineurin were previously found in some schizophrenia patients. Ten years ago, MIT researchers removed this gene in mice which caused them to exhibit several behavioral symptoms like those of schizophrenia, including impaired short-term memory, attention deficits and abnormal social behavior.
These researchers now find that mice lacking calcineurin have hyperactive brain-wave oscillations in the hippocampus while resting, and are unable to mentally replay a route they have just run, as normal mice do.
In the new study, led by Susumu Tonegawa, Ph.D., the Picower Professor of Biology and Neuroscience, recorded the electrical activity of individual neurons in the hippocampus of these altered mice as they ran along a track.
Prior research on normal mice has shown that “place cells” in the hippocampus (linked to specific locations along the track) fire in sequence when the mice rest after running the course. This mental replay also occurs when the mice are sleeping, and they are tied to very high frequency brain-wave oscillations known as ripple events.
In mice lacking calcineurin, the researchers found that brain activity appeared normal while they ran the course, but when they paused, their ripple events were much stronger and more frequent. Plus the firing of the place cells was abnormal and in no particular order, suggesting the mice were not replaying the route they had just run.
This pattern helps to explain some of the symptoms seen in schizophrenia, said the researchers.
“We think that in this mouse model, we may have some kind of indication that there’s a disorganized thinking process going on,” said Dr. Junghyup Suh, a research scientist at the Picower Institute and one of the paper’s lead authors.
“During ripple events in normal mice we know there is a sequential replay event. This mutant mouse doesn’t seem to have that kind of replay of a previous experience.”
The researchers suspect that in normal mice, calcineurin suppresses the connections between neurons (synapses) in the hippocampus. In mice without calcineurin, a phenomenon known as long-term potentiation (LTP) becomes more common, making synapses stronger.
“It looks like this abnormally high LTP has an impact on activity of these cells specifically during resting periods, or post exploration periods. That’s a very interesting specificity,” Tonegawa said. “We don’t know why it’s so specific.”
The researchers think the abnormal hyperactivity in the hippocampus may signify a disruption of the brain’s “default mode network” — a communication network that connects the hippocampus, prefrontal cortex (where most thought and planning occurs), and other areas of the cortex.
This network is more active during a restful state, between goal-oriented tasks. When the brain is focusing on a specific activity, the default mode network gets turned down. This network, however, is over-active in schizophrenic patients before and during tasks that require focus, and patients do not perform well in these tasks.
More research on mice could help reveal more about the role of the default mode network in schizophrenia, Tonegawa said.