Impaired brain glucose metabolism and presynaptic dopaminergic functioning in a mouse model of schizophrenia

Eugenia Tomasella,German Falasco,Lucila Bechelli,Leandro Urrutia,Diego M Gelman,Lucia Padilla

doi:10.1186/s13550-020-00629-x

Abstract

BackgroundSchizophrenia 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.ResultsMutant 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.ConclusionsDopamine 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.

Highlights

Schizophrenia is a disease diagnosed by visible signs and symptoms from late adolescence to early adulthood
These symptoms are well treated by the administration of antipsychotics, which are antagonists of dopamine D2 receptors (DRD2) [2]
Our results show that tyrosine hydroxylase (TH) expression is reduced in the ventral tegmental area (VTA) region of mutant animals but not in the substantia nigra compacta

Summary

Introduction

Schizophrenia is a disease diagnosed by visible signs and symptoms from late adolescence to early adulthood. Schizophrenia is a syndrome of still unknown etiology that affects 1% of world population It is diagnosed between late adolescence and early adulthood only by visible signs and symptoms [1]. A reduction in dopamine tone in prefrontal cortex is accompanied by an increased dopamine tone in the striatum, underling negative and positive symptoms of the disease, respectively [3] In this context, antipsychotic blockade of D2 receptors in the striatum might prevent excessive DRD2 signaling. Post-mortem studies from schizophrenia patients have shown a reduced expression of the ratelimiting enzyme of dopamine synthesis, tyrosine hydroxylase (TH) in midbrain dopaminergic neurons [4] This observation was associated to the prefrontal hypodopaminergic state.

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Discussion

Conclusion