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Impaired Brain Connections Traced to Schizophrenia Mutation

Mouse at the decision point in the T-maze. Dr. Torfi Sigurdsson, Columbia University.

The strongest known genetic cause of schizophrenia impairs communication between 2 brain regions and affects working memory, according to a study in mice.

Schizophrenia is a chronic, severe and disabling brain disorder that affects about 1% of adults nationwide every year. People with schizophrenia sometimes hear voices others don’t hear, believe that others are broadcasting their thoughts to the world, or become convinced that others are plotting to harm them. These experiences can make them fearful and withdrawn and cause difficulties with relationships.

Over a century ago, researchers proposed that a disturbance in the connectivity between brain areas underlies schizophrenia. Past neuroimaging studies have linked abnormal connections between the brain's prefrontal cortex (the executive hub) and the hippocampus (the memory hub) to impaired working memory, one of the functions that are disrupted in schizophrenia.

Although schizophrenia is thought to be 70% heritable, its genetics are dauntingly complex, except in certain rare cases. A mutation called 22q11.2 has previously been shown to boost schizophrenia risk 30-fold, in addition to causing other abnormalities. Although accounting for only a small portion of cases, this tiny missing section of genetic material, called a microdeletion, has repeatedly turned up in genetic studies of schizophrenia and is an indisputable risk factor for the illness.

A research team at Columbia University led by Dr. Joshua Gordon, Dr. Joseph Gogos and Dr. Maria Karayiorgou set out to explore the mutation's link to disturbed connectivity and working memory problems. Funded by NIH's ×îÐÂÂ鶹ÊÓƵ Institute of Mental Health (NIMH), along with the Simons Foundation and the Lieber Center for Schizophrenia Research and Treatment, the scientists engineered a line of mice with the mouse equivalent of the 22q11.2 microdeletion.

The team tested the mice’s working memory in a simple T-maze task, in which the mice had to decide which arm of the maze to go in. To measure the connection between the prefrontal cortex and the hippocampus, the researchers monitored signals emitted by single neurons in the 2 distant brain structures while the mice performed the T-maze task.

In the April 1, 2010, issue of Nature, the scientists reported that, similar to humans with schizophrenia, the mice turned out to have difficulty with the working memory task. They learned much more slowly and had lower performance levels than control mice.

The mice also had much worse synchrony between the brain regions than control mice. In general, the more in-sync the neurons from the 2 areas fired, the researchers found, the better the mice performed the task. Moreover, the better the synchrony between brain regions to start with, the quicker the animals learned the task.

"Our results extend beyond those in patients by showing how an undeniable genetic risk factor for schizophrenia can disrupt connectivity at the level of single neurons," Gordon says. The researchers plan to follow up with studies into how the mutation affects the brain's structure and molecular connections. They also plan to examine affected genes.