Modulation of hippocampal theta and hippocampal‐prefrontal cortex function by a schizophrenia risk gene

Hippocampal theta‐band oscillations are thought to facilitate the co‐ordination of brain activity across distributed networks, including between the hippocampus and prefrontal cortex (PFC). Impairments in hippocampus‐PFC functional connectivity are implicated in schizophrenia and are associated with a polymorphism within the ZNF804A gene that shows a genome‐wide significant association with schizophrenia. However, the mechanisms by which ZNF804A affects hippocampus‐PFC connectivity are unknown. We used a multimodal imaging approach to investigate the impact of the ZNF804A polymorphism on hippocampal theta and hippocampal network coactivity. Healthy volunteers homozygous for the ZNF804A rs1344706 (A[risk]/C[nonrisk]) polymorphism were imaged at rest using both magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI). A dual‐regression approach was used to investigate coactivations between the hippocampal network and other brain regions for both modalities, focusing on the theta band in the case of MEG. We found a significant decrease in intrahippocampal theta (using MEG) and greater coactivation of the superior frontal gyrus with the hippocampal network (using fMRI) in risk versus nonrisk homozygotes. Furthermore, these measures showed a significant negative correlation. Our demonstration of an inverse relationship between hippocampal theta and hippocampus‐PFC coactivation supports a role for hippocampal theta in coordinating hippocampal‐prefrontal activity. The ZNF804A‐related differences that we find in hippocampus‐PFC coactivation are consistent with previously reported associations with functional connectivity and with these changes lying downstream of altered hippocampal theta. Changes in hippocampal‐PFC co‐ordination, driven by differences in oscillatory activity, may be one mechanism by which ZNF804A impacts on brain function and risk for psychosis. Hum Brain Mapp 36:2387–2395, 2015. © 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.