Hippocampal-prefrontal connectivity as a translational phenotype for schizophrenia

Finding novel biological targets in psychiatry has been difficult, partly because current diagnostic categories are not defined by pathophysiology and difficult to model in animals. The study of species-conserved systems-level mechanisms implicated in psychiatric disease could be a promising strategy to address some of these difficulties. Altered hippocampal-prefrontal (HC-PFC) connectivity during working memory (WM) processing is a candidate for such a translational phenotype as it has been repeatedly associated with impaired cognition in schizophrenia patients and animal models for psychiatric risk factors. Specifically, persistent hippocampus-dorsolateral prefrontal cortex (HC-DLPFC) coupling during WM is an intermediate phenotype for schizophrenia that has been observed in patients, healthy relatives and carriers of two different risk polymorphisms identified in genome-wide association studies. Rodent studies report reduced coherence between HC and PFC during anesthesia, sleep and task performance in both genetic, environmental and neurodevelopmental models for schizophrenia. We discuss several challenges for translation including differences in anatomy, recording modalities and WM paradigms and suggest that a better understanding of HC-PFC coupling across species can be achieved if translational neuroimaging is used to control for task differences. The evidence for potential neurobiological substrates underlying HC-PFC dysconnectivity is evaluated and research strategies are proposed that aim to bridge the gap between findings from large-scale association studies and disease mechanisms.