Ventral Hippocampus, Interneurons, and Schizophrenia: A New Understanding of the Pathophysiology of Schizophrenia and Its Implications for Treatment and Prevention

Dysfunction within the dopamine system has been the predominant hypothesized cause of schizophrenia for some time; however, there is little anatomical or postmortem evidence showing that the roots of this disorder are to be found within the dopaminergic neurons. Instead, the dopamine system appears to be dysregulated due to pathological influences from other structures. Recent postmortem and imaging studies have looked to the hippocampus as a potential site of this pathology. Our studies using a developmental animal model of schizophrenia found hyperactivity in the hippocampus likely drives the disruption in dopamine system function. This overactivity appears to be due to the functional loss of short axon interneurons that control the activity of the primary output neurons of the hippocampus. These data suggest that a more effective treatment of schizophrenia may be to normalize hippocampal function rather than block dopamine receptors. Moreover, given the high sensitivity of the hippocampus to stress-induced damage and the fact that stress is a risk factor for schizophrenia, controlling stress in the premorbid state may be an effective preventative measure to circumvent the transition to psychosis.