Excessive dopamine neurotransmission underlies psychotic episodes as observed in patients with some types of bipolar disorder and schizophrenia. The dopaminergic hypothesis was postulated after the finding that antipsychotics were effective to halt increased dopamine tone. However, there is little evidence for dysfunction within the dopaminergic system itself. Alternatively, it has been proposed that excessive afferent activity onto ventral tegmental area dopaminergic neurons, particularly from the ventral hippocampus, increase dopamine neurotransmission, leading to psychosis. Here, we show that selective dopamine D receptor deletion from parvalbumin interneurons in mouse causes an impaired inhibitory activity in the ventral hippocampus and a dysregulated dopaminergic system. Conditional mutant animals show adult onset of schizophrenia-like behaviors and molecular, cellular, and physiological endophenotypes as previously described from postmortem brain studies of patients with schizophrenia. Our findings show that dopamine D receptor expression on parvalbumin interneurons is required to modulate and limit pyramidal neuron activity, which may prevent the dysregulation of the dopaminergic system.
Background: Schizophrenia is a disease diagnosed by visible signs and symptoms from late adolescence to early adulthood. The etiology of this disease remains unknown. An objective diagnostic approach is required. Here, we used a mouse model that shows schizophrenia-like phenotypes to study brain glucose metabolism and presynaptic dopaminergic functioning by positron emission tomography (PET) and immunohistochemistry. PET scannings were performed on mice after the administration of [ 18 F]-FDG or [ 18 F]-F-DOPA. Glucose metabolism was evaluated in basal conditions and after the induction of a hyperdopaminergic state. Results: Mutant animals show reduced glucose metabolism in prefrontal cortex, amygdala, and nucleus reuniens under the hyperdopaminergic state. They also show reduced [ 18 F]-F-DOPA uptake in prefrontal cortex, substantia nigra reticulata, raphe nucleus, and ventral striatum but increased [ 18 F]-F-DOPA uptake in dorsal striatum. Mutant animals also show reduced tyrosine hydroxylase expression on midbrain neurons. Conclusions: Dopamine D2 mutant animals show reduced glucose metabolism and impaired presynaptic dopaminergic functioning, in line with reports from human studies. This mouse line may be a valuable model of schizophrenia, useful to test novel tracers for PET scanning diagnostic.
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