The strongest known recurrent（周期性的，复发的） genetic cause of schizophrenia（精神分裂症） impairs communications between the brain's decision-making and memory hubs（枢纽，中心） , resulting in working memory deficits, according to a study in mice. "For the first time, we have a powerful animal model that shows us how genetics affects brain circuitry（电路，线路） , at the level of single neurons（神经原，神经细胞） , to produce a learning and memory deficit linked to schizophrenia," explained Thomas R. Insel, M.D., director of the National Institute of Mental Health (NIMH), part of the National Institutes of Health. "This new research tool holds promise for ultimately unraveling（解开，阐明） the underlying anatomical（解剖的，结构上的） connections and specific genes involved."

NIMH grantees Joshua Gordon, M.D., Ph.D., Joseph Gogos, M.D., Ph.D., Maria Karayiorgou, M.D., and Columbia University colleagues, report on their discovery in genetically engineered mice in the April 1, 2010 issue of the journal Nature.

"Our findings pinpoint（查明） a specific circuit and mechanism by which a mutation produces a core feature of the disorder," said Gordon, who led the research.

Researchers have suspected such a brain connectivity disturbance in schizophrenia for more than a century, and the NIH has launched a new initiative（主动权，首创精神） on the brain's functional circuitry, or connectome（连接体） . Although the disorder is thought to be 70 percent heritable（可继承的） , its genetics are dauntingly（令人生畏地，吓人地） complex, except in certain rare cases, such as those traced to the mutation in question.

Prior to this study, neuroimaging（神经成像） studies in schizophrenia patients had found abnormal connections between the brain's prefrontal（前额的） cortex（皮质，树皮） , the executive hub, and the hippocampus（海马体） , the memory hub, linked to impaired working memory. It was also known that a mutation in the suspect site on chromosome 22, called 22q11.2, boosts schizophrenia risk 30-fold and also causes other abnormalities). Although accounting for only a small portion of cases, this tiny missing section of genetic material, called a microdeletion（缺失） , has repeatedly turned up in genetic studies of schizophrenia and is an indisputable（明白的） risk factor for the illness.

Still, the mutation's link to the disturbed connectivity and working memory deficit eluded（逃避，躲避） detection until now.

To explore the mutation's effects on brain circuitry, Gogos, Karayiorgou and colleagues engineered a line of mice expressing the same missing segment of genetic material as the patients. Strikingly, like their human counterparts with schizophrenia, these animals turned out to have difficulty with working memory tasks – holding information in mind from moment to moment.

Successful performance of such tasks depends on good connections in a circuit linking the prefrontal cortex and the hippocampus. To measure such functional connections, Gordon and colleagues monitored signals emitted by single neurons implanted in the two distant brain structures while mice performed a working memory task in a T-maze.

The more in-sync the neurons from the two areas fired, the better the functional connections between the two structures – and the better the mice performed the task. Moreover, the better the synchrony to start with, the quicker the animals learned the task. The more synchrony（同步） improved, the better they performed.

As suspected, the mice with the chromosome（染色体） 22 mutation faltered on all counts -- showing much worse synchrony, learning and performance levels than control mice.

"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," explained Gordon.

The researchers plan to follow up with studies into how the mutation affects brain anatomical and molecular connections and the workings of affected genes.