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.