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

Abstract

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.

Neurobiological substrates underlying corpus callosum hypoconnectivity and brain metabolic patterns in the valproic acid rat model of autism spectrum disorder

“…Images were reconstructed using an ordered subsets expectation maximization 3D algorithm with 30 iterations to maximize signal‐to‐noise ratio. Motion correction was applied by performing dynamic reconstruction using a statistical parametric mapping (SPM5) on MATLAB ® (Matrix Laboratory) realign algorithm (Tomasella et al., 2020).…”

Caffeine-Induced Acute and Delayed Responses in Cerebral Metabolism of Control and Schizophrenia-like Wisket Rats

“…While our recent morphometric study on Wisket rats proved moderately decreased brain volume, it was not accompanied by altered metabolic brain activity at the whole-brain level and in the investigated cerebral structures [ 24 ]. Regarding the earlier preclinical studies of brain metabolism in single-hit schizophrenia models, inconsistent data are available [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 42 ]. The in vitro autoradiography studies have found increased glucose metabolism in several brain structures (e.g., ventral tegmental area, substantia nigra, and hypothalamus) but not in the hippocampus, some cortical areas or thalamus in STOP protein mutant mice, or after a neonatal hippocampal lesion [ 9 , 10 ].…”

“…In contrast, mGluR5 mutant mice showed no differences in the baseline SUV values in the investigated brain areas (cortex, hippocampus, thalamus striatum, cerebellum, and the whole brain) compared to controls [ 11 ]. The selective dopamine D 2 receptor deletion from parvalbumin positive interneurons caused decreased metabolism in the somatosensory/insular cortex and lateral hypothalamic areas, but augmented glucose utilization was detected in the basolateral amygdala [ 6 ]. Additionally, post-weaning isolation rearing resulted in a reduced metabolic rate in the hippocampus and thalamus [ 42 ].…”

“…Importantly, in agreement with the 3Rs (Replacement, Reduction, and Reinforcement) of animal research, we did not involve saline-treated control groups, since PET had a good level of test–retest stability, and the order of different interventions did not influence the brain glucose uptake [ 6 , 8 , 11 , 68 , 69 ].…”

“…Conflicting results have been reported on altered metabolism in various brain structures in schizophrenia patients by PET studies [ 1 , 2 , 3 , 4 , 5 ]. While preclinical models cannot represent the full picture of schizophrenia (e.g., most of the positive symptoms of schizophrenia request verbal report to be measured properly), preclinical studies also suggest changes in brain metabolism by using various single-hit animal models of schizophrenia, including maternal immune activation, neonatal hippocampal lesion, the administration of NMDA receptor antagonists, mutant mice of D 2 dopamine or metabotropic glutamate 5 (mGluR5) receptors, or microtubule-associated protein (STOP: stable tubule only peptide) [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ].…”