RESUMO
Abnormal dopamine neurotransmission is a common trait of some psychiatric diseases, like schizophrenia or bipolar disorder. Excessive dopaminergic tone in subcortical brain regions is associated with psychotic episodes, while reduced prefrontal dopaminergic activity is associated with impaired cognitive performance and reduced motivation, among other symptoms. Inhibitory interneurons expressing the calcium binding protein parvalbumin are particularly affected in both schizophrenia and bipolar disorder, as they set a fine-tuned physiological inhibitory/excitatory balance. Parvalbumin and somatostatin interneuron subtypes, are born from the medial ganglionic eminence and require the sequential expression of specific transcription factors for their specification, such as Nkx6.2. Here, we aimed at characterizing in detail interneuron subtypes derived from Nkx6.2 expressing progenitors by the generation of an Nkx6.2 Cre transgenic mouse line. We show that Nkx6.2 specifies over a third part of the total population of cortical somatostatin interneurons, preferentially at early developmental time points, whereas at late developmental stages, Nkx6.2 expressing progenitors shift to parvalbumin interneuron specification. Dopamine D2 receptor deletion from Nkx6.2 expressing progenitors causes abnormal phenotypes restricted to cognitive, motivation and anxiety domains. Our results show that Nkx6.2 have the potential to specify both somatostatin and parvalbumin interneurons in an opposite timed program and that DRD2 expression is required in Nkx6.2 expressing progenitors to avoid impaired phenotypes commonly associated to the pathophysiology of psychiatric diseases.
Assuntos
Motivação , Parvalbuminas , Animais , Camundongos , Ansiedade/genética , Cognição , Interneurônios/metabolismo , Camundongos Transgênicos , Parvalbuminas/metabolismo , Fenótipo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Somatostatina/genética , Somatostatina/metabolismoRESUMO
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 [18F]-FDG or [18F]-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 [18F]-F-DOPA uptake in prefrontal cortex, substantia nigra reticulata, raphe nucleus, and ventral striatum but increased [18F]-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.
RESUMO
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 D2 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 D2 receptor expression on parvalbumin interneurons is required to modulate and limit pyramidal neuron activity, which may prevent the dysregulation of the dopaminergic system.