Dopamine system dysregulation by the hippocampus: implications for the pathophysiology and treatment of schizophrenia

For decades, the predominant hypothesis of schizophrenia centered on dysfunctions of the dopamine system. However, recent evidence now suggests that the dopamine system may be "normal" in its configuration, but instead is regulated abnormally by modulatory processes. Convergent studies in animals and in humans have now focused on the hippocampus as a central component in the generation of psychosis and possibly other symptom states in schizophrenia. Thus, activity in the ventral hippocampus has been shown to regulate dopamine neuron responsivity by controlling the number of dopamine neurons that can be phasically activated by stimuli. In this way, this structure determines the gain of the dopamine signal in response to stimuli. However, in schizophrenia, the hippocampus appears to be hyper-active, possibly due to attenuation of function of inhibitory interneurons. As a result, the dopamine system is driven into an overly responsive state. Current medications have focused on blockade of overstimulated dopamine receptors; however, this now appears to be several synapses downstream from the pathological antecedent. Therapeutic approaches that focus on normalizing hippocampal function may prove to be more effective treatment avenues for the schizophrenia patient.