Opinion
Hippocampal dysregulation of dopamine system function and the pathophysiology of schizophrenia

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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 D2 receptors. Indeed, initial studies demonstrate that allosteric modulation of the α5GABAA receptor can decrease aberrant dopamine signaling and associated behaviors in a verified rodent model of psychosis.

Section snippets

Schizophrenia

Schizophrenia has a prevalence of ∼0.8% of the population and a lifetime prevalence of ∼1% [1]. It is characterized by three classes of signs and symptoms; positive, negative and cognitive. These are initially reported based on whether the sign or symptom was in addition to (positive), or absent from (negative), normal behavior [2]. Thus, positive symptoms of the disease include hallucinations, delusions and disorganized thoughts, whereas negative signs consist of anhedonia and social

Dopamine hypothesis of schizophrenia

The neurotransmitter system that has been most commonly associated with schizophrenia is the dopamine system. This ‘dopamine hypothesis’ is one of the longest-standing hypotheses of schizophrenia. It is based on multiple observations linking dopamine dysregulation to the pathophysiology of the disease. This includes the finding that enhanced activity within the subcortical dopamine system is associated with the positive symptoms of schizophrenia 4, 5 and the fact that all antipsychotic

Altered hippocampal function in schizophrenia

The hippocampus is a temporal lobe structure essential for the consolidation of long-term memories. Deficits in the structure and function of the hippocampus are a consistent observation in imaging and post-mortem studies from schizophrenia patients [14]. Specifically, one of the more constant findings from imaging studies is that patients cannot recruit the hippocampus during a task (i.e. memory recall) 15, 16. Further evidence for hippocampal dysfunction came from structural imaging and

Hippocampal regulation of the function of the dopamine system

The consequence of the purported hippocampal hyperactivity in schizophrenia patients is not entirely known. However, activation of the ventral hippocampus (vHipp) increases dopamine efflux throughout the nucleus accumbens (NAc) of anesthetized rats 26, 27. Thus, chemical or electrical stimulation of the vHipp produces sustained increases in extrasynaptic dopamine throughout the NAc, a principal target of dopamine neurons 26, 27. The mechanisms underlying these effects were not immediately

Depolarization block hypothesis of antipsychotic medications

All current antipsychotic medications have antagonist actions at the dopamine D2 receptor. However, it is evident that antipsychotic drugs achieve their effects via mechanisms that are more complex than the simple blockade of dopamine receptors. Thus, although the maximum rate of improvement occurs early in treatment 38, 39, 40, 41, patients also require several weeks of treatment to reach maximum therapeutic responses [38] without evidence of tolerance (as one would expect from simple receptor

The hippocampus as a novel therapeutic target

Although conventional antipsychotic medications might effectively decrease the positive symptoms of schizophrenia, they are not particularly effective at treating negative signs and cognitive symptoms. This largely reflects the mechanism of action of D2 antagonists. A decrease in dopamine neuron population activity due to depolarization block will reduce the ascribed salience of the dopamine signal. However, it achieves this not by reversing the proposed vHipp overdrive, but instead by inducing

Concluding remarks

There is increasing evidence from preclinical and human imaging studies suggesting that augmented hippocampal function secondary to a loss of interneuron function underlies the dopamine hyperfunction associated with psychosis in schizophrenia. Thus, restoration of hippocampal function might provide a novel therapeutic target for treatment of the disease. Indeed, our recent data demonstrate that a positive allosteric modulator of the α5GABAA receptor can reverse aberrant dopamine system function

Acknowledgments

Dr. Grace has the following financial disclosures: Johnson & Johnson, Lundbeck, Pfizer, GSK, Puretech Ventures, Merck, Takeda, and Dainippon Sumitomo. Dr. Lodge has no conflicts of interest to report.

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