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.