Hippocampal dysregulation of dopamine system function and the pathophysiology of schizophrenia

Substantial evidence suggests that psychosis in schizophrenia is associated with dysregulation of subcortical dopamine system function. Here we examine evidence that this dysregulation is secondary to hyperactivity within hippocampal subfields. Enhanced hippocampal activity has been reported in preclinical models and in schizophrenia patients. Moreover, this hippocampal hyperactivity is correlated with enhanced dopamine neuron activity and positive symptoms, respectively. Thus, restoration of hippocampal function could provide a more effective therapeutic approach than current therapeutics based on blockade of dopamine 02 receptors. Indeed, initial studies demonstrate that allosteric modulation of the alpha 5GABA(A) receptor can decrease aberrant dopamine signaling and associated behaviors in a verified rodent model of psychosis.