In vivo glucose metabolism and glutamate levels in mGluR5 knockout mice: a multimodal neuroimaging study using [18F]FDG microPET and MRS

Abstract

Background Perturbed functional coupling between the metabotropic glutamate receptor-5 (mGluR5) and N-methyl-d-aspartate (NMDA) receptor-mediated excitatory glutamatergic neurotransmission may contribute to the pathophysiology of psychiatric disorders such as schizophrenia. We aimed to establish the functional interaction between mGluR5 and NMDA receptors in brain of mice with genetic ablation of the mGluR5. Methods We first measured the brain glutamate levels with magnetic resonance spectroscopy (MRS) in mGluR5 knockout (KO) and wild-type (WT) mice. Then, we assessed brain glucose metabolism with [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography before and after the acute administration of an NMDA antagonist, MK-801 (0.5 mg/kg), in the same mGluR5 KO and WT mice. Results Between-group comparisons showed no significant differences in [18F]FDG standardized uptake values (SUVs) in brain of mGluR5 KO and WT mice at baseline, but widespread reductions in mGluR5 KO mice compared to WT mice after MK-801 administration (p < 0.05). The baseline glutamate levels did not differ significantly between the two groups. However, there were significant negative correlations between baseline prefrontal glutamate levels and regional [18F]FDG SUVs in mGluR5 KO mice (p < 0.05), but no such correlations in WT mice. Fisher’s Z-transformation analysis revealed significant between-group differences in these correlations (p < 0.05). Conclusions This is the first multimodal neuroimaging study in mGluR5 KO mice and the first report on the association between cerebral glucose metabolism and glutamate levels in living rodents. The results indicate that mGluR5 KO mice respond to NMDA antagonism with reduced cerebral glucose metabolism, suggesting that mGluR5 transmission normally moderates the net effects of NMDA receptor antagonism on neuronal activity. The negative correlation between glutamate levels and glucose metabolism in mGluR5 KO mice at baseline may suggest an unmasking of an inhibitory component of the glutamatergic regulation of neuronal energy metabolism.

Dorsal striatal dopamine induces fronto-cortical hypoactivity and implies reduced anxiety and compulsive behaviors in rats

“…As noted above, there is no general model to connect glutamate levels measured with MRS to [ 18 F]FDG uptake. One study reported no correlation between these two markers in WT mice, although there was a clear inverse relationship in mGluR5 KO mice [79]. That finding resembles present observations in the mDS-DREADD group, suggesting a similar perturbation of the coupling between glutamate levels and energy metabolism.…”

“…Furthermore, we suppose that DS-DQ stimulation also stimulate dopamine neurons that co-release glutamate (83, 84) , which in turn might favor the astroglial conversion of glutamine to glutamate (80, 81) . There is no general model to connect glutamate levels measured with MRS to [ 18 F]FDG uptake, and these two markers did no correlate in WT mice, although there was a clear inverse relationship in mGluR5 KO mice (85) . That finding resembles present findings in the DS-DQ group, suggesting a similar perturbation of the coupling between glutamate levels and energy metabolism.…”

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 ].…”

“…Chronic treatment with an NMDA receptor antagonist caused decreased metabolism in all the detected brain regions (caudate putamen, medial prefrontal cortex, cingulate cortex, and hippocampus) [ 8 ]. 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 ].…”

“…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 ].…”