title: Modulation of hippocampal theta and hippocampal-prefrontal cortex function by a schizophrenia risk gene.
abstract: 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.
authors.affiliation: Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford,, United Kingdom; Oxford Centre for Human Brain Activity, University of Oxford, Warneford Hospital, Oxford, United Kingdom.
authors.forename: Helena
authors.initials: H
authors.lastname: Cousijn
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Tunbridge
authors.forename: Michal
authors.initials: M
authors.lastname: Rolinski
authors.forename: George
authors.initials: G
authors.lastname: Wallis
authors.forename: Giles L
authors.initials: GL
authors.lastname: Colclough
authors.forename: Mark W
authors.initials: MW
authors.lastname: Woolrich
authors.forename: Anna C
authors.initials: AC
authors.lastname: Nobre
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Harrison
mesh_terms: D000293:Adolescent; D000328:Adult; D001931:Brain Mapping; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006624:Hippocampus / Q000502:physiology*; D006720:Homozygote; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D015225:Magnetoencephalography; D009434:Neural Pathways / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000502:physiology*; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology; D013826:Theta Rhythm / Q000502:physiology*; D055815:Young Adult
chemical_list: D051741:Kruppel-Like Transcription Factors; C540527:ZNF804A protein, human
keywords: ZNF804A; functional magnetic resonance imaging; hippocampus; magnetoencephalography; oscillation; psychosis