Hippocampal Dysregulation of Dopamine System Activity as a Pathophysiological Basis for Psychosis in Schizophrenia

다국어 초록 (Multilingual Abstract)

For over 40 years, the dominant hypothesis of schizophrenia has been based on deficits leading to overstimulation by dopamine.
In recent years, however, there has been a shift from a primary dopamine deficit to a dysfunction involving cortical regulation of the dopamine system. Current research represents a remarkable convergence of both clinical research and basic animal studies into the pathophysiology of schizophrenia. Thus, clinical studies have detailed a dopamine system that is hyper-responsive to inputs, and hyperactivity in the hippocampus that correlates with psychosis. Experiments in developmental animal models have shown that hyperactivity within the hippocampus subiculum drives an increase in dopamine neuron population activity that underlies the abnormally high responsivity of the dopamine system to stimuli. In both human studies and animal models, there is a corresponding loss of parvalbumin interneurons in the prefrontal cortex and the hippocampus, and this correlates with the loss of evoked gamma oscillatory rhythms in both subjects. Therefore, a model emerges in which a loss of activity within a selective interneuron population as observed postmortem in schizophrenia patients as well as in a developmental animal model of schizophrenia leads to disorganized hyper-activity within the hippocampus. This in turn renders the dopamine system hyper-responsive to stimuli, causing an inordinate attribution of attention and salience to all stimuli independent of their functional significance. These studies suggest that a more effective therapeutic strategy would involve restoration of hippocampal activity states via modulation of interneuron regulation.

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