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Recent advances have identified over one hundred genes that affect a person’s risk of developing schizophrenia. However, in most cases the pathways linking these individual genes with whole brain function are unclear. A new study from researchers in the Oxford Centre for Human Brain Activity (OHBA) suggests that the link between one gene, known as ZNF804A, and schizophrenia arises from its effects on rhythmic brain activity.

Rhythmic activity patterns provide a means for encoding information in the brain and are abnormal in patients with schizophrenia.  One type of brain rhythm, theta activity, is generated in a region called the hippocampus and co-ordinates activity across the whole brain, allowing networks of brain regions to work together efficiently. The study compared activity in the hippocampus measured using two types of brain imaging, fMRI and MEG, between healthy people who carry the schizophrenia-risk form of ZNF804A, with those who do not. Using MEG, the researchers showed for the first time that the ZNF804A gene variant influences theta activity in the hippocampus. This is the first time that a schizophrenia risk gene variant has been shown to do this. Using fMRI, and consistent with earlier studies, they also showed that ZNF804A influences the co-ordination of activity between the hippocampus and prefrontal cortex, another brain region known to be important in schizophrenia. Crucially, they found that theta activity in the hippocampus predicted the co-ordination of activity in the hippocampus and prefrontal cortex. Therefore, they suggest that the effects of ZNF804A on rhythmic theta activity might drive changes in the co-ordination activity between the hippocampus and prefrontal cortex. This is of significant interest as alterations in the co-ordination of these two brain regions is a key feature of schizophrenia and is thought to drive some of the symptoms from which patients suffer.

Therefore, these findings provide details of how ZNF804A might alter risk for schizophrenia; namely, by influencing theta activity and thus hippocampus-prefrontal cortex co-ordination. They also suggest that future studies should focus on the role of ZNF804A in regulating the specific brain cells and circuits that are known to be involved in generating theta activity in the hippocampus. Ultimately, understanding the molecules, cells and circuits that are altered in schizophrenia might provide new drug targets to treat the symptoms suffered by patients.

The study was conducted by Helena Cousijn and Liz Tunbridge, led by Kia Nobre and Paul Harrison, and has just been published in Human Brain Mapping.  It is freely available to read online: http://onlinelibrary.wiley.com/doi/10.1002/hbm.22778/pdf