New evidence suggests that schizophrenia can be caused by a lack of synchronization between regions of the brain.
Mice with a genetic defect linked to schizophrenia had trouble navigating through a maze.
Mice with a genetic defect linked to schizophrenia had trouble navigating through a maze. iStockphoto.com
In a study, just published in the journal Nature, researchers from Columbia University compared mice bred to have a genetic mutation linked to schizophrenia in humans with healthy mice and found that mutant mice had more trouble completing spatial tasks — like getting through a maze.
Though most people associate schizophrenia most strongly with hallucinations and delusions, the disease also impairs cognitive abilities, including working memory. The Columbia researchers found that the two regions of the brain associated with working memory in the mutant mice — the hippocampus and the prefrontal cortex — weren't communicating the way they do in normal animals.
The short circuit may lend a clue to the causes of schizophrenia in humans.
Shots caught up with Dr. Joshua Gordon, a psychiatrist at Columbia University Medical Center and a senior author of the study, to learn more. Here are edited highlights from the interview.
How did you get interested in this line of research?
Obviously when you have a gene that you've identified that contributes to an illness — especially a psychiatric illness — that's the first step to understanding how the disease develops.
So, we first started with this gene that's very clearly associated to schizophrenia — this particular gene is actually a deletion of 20-some-odd genes that gives individuals at 30 percent greater risk for developing schizophrenia. That's the strongest link of any gene.
And so we looked at mice that were lacking those same genes. They had some of the cognitive deficits that schizophrenic patients have. In particular, we studied working memory. That's the ability to hold information for short periods of time and then use it to complete tasks.
And how was the experiment carried out?
We asked the mice to hold spatial information in their memory and use it to help decide their way through a maze. And we found that the mice carrying the deletion can't do that as well.
What intrigued me is that this kind of behavior is actually one that we know a whole lot about. The hippocampus and the prefrontal cortex need to communicate with each other to complete the tasks we're asking the mice to do. So, we wondered if the connections between these two regions weren't working as well in these mice, and we attached electrodes to the mice to see those connections.
In normal mice, the hippocampus and the prefrontal cortex work together during the task — the activity becomes synchronized. In the mutant mice, the activity between the two areas did not become synchronized to the same extent; they weren't able to use these two areas together.
Whether the wiring is incorrect or if the wiring is there but not functional, the link between the two areas cannot be established to the same degree.
But we were also able to show that, for each individual animal, the mutants that had more difficulty synchronizing the two areas had more difficulty doing the behavioral task. So this isn't two different phenomena — a behavioral one and one in brain communication. They're linked.
Is this genetic deletion that predisposes humans to schizophrenia the same one in mice?
It's as identical as we could possibly make it. Ninety-five percent of the genes deleted in the human are deleted in the mice.
So how can you reconcile these findings in mice with the what to expect in humans?
People have looked at connectivity between brain regions and schizophrenia before. In fact, the hypothesis that the brain regions can't communicate as a cause for schizophrenia has been around for 100 years. What this study does is move it along and says that this particular gene leads to this particular dysfunction in connectivity between these particular brain regions.
This also tells us that in the subset of schizophrenics who carry this mutation, it's quite likely that they have connectivity problems between these brain regions. That gives us two ways to go forward. Now that we know which brain regions and which populations of patients to look at, we can use imaging techniques to verify this model found in the mice. We now know what specific questions we need to be asking.
If we verify that this is the case, we can use the mice to develop a treatment that will enhance the ability of the brain regions to communicate and then take that back to humans.
Are there any such treatments that focus on brain connectivity?
Actually, no. And that's a big problem in the treatment of schizophrenia right now. Our treatments are very good at helping the most obvious symptoms — hallucinations and all — but the treatments don't help make brain function more fluid.
Many schizophrenic patients may not be hearing voices, but they may have trouble balancing a checkbook or taking the Metro — cognitive problems — and we don't have treatments for this. So, if we could develop treatments [to improve cognition] we could really change the lives of many schizophrenic patients today.