Reduced mGluR5 Activity Modulates Mitochondrial Function

Cells

Joke Wortel¹  Jan R. T. van Weering¹  August B. Smit²  Rolinka J. van der Loo²  Ka Wan Li²  Miguel A. Gonzalez-Lozano² 

[1] Center for Neurogenomics and Cognitive Research, Department of Functional Genomics, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, 1081 Amsterdam, The Netherlands;Center for Neurogenomics and Cognitive Research, Department of Molecular and Cellular Neurobiology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, 1081 Amsterdam, The Netherlands;

关键词: proteomics;    mGluR5;    mitochondria;    mass spectrometry;    synapse;    CTEP;   

DOI  :  10.3390/cells10061375

来源: DOAJ

【 摘 要 】

The metabotropic glutamate receptor 5 (mGluR5) is an essential modulator of synaptic plasticity, learning and memory; whereas in pathological conditions, it is an acknowledged therapeutic target that has been implicated in multiple brain disorders. Despite robust pre-clinical data, mGluR5 antagonists failed in several clinical trials, highlighting the need for a better understanding of the mechanisms underlying mGluR5 function. In this study, we dissected the molecular synaptic modulation mediated by mGluR5 using genetic and pharmacological mouse models to chronically and acutely reduce mGluR5 activity. We found that next to dysregulation of synaptic proteins, the major regulation in protein expression in both models concerned specific processes in mitochondria, such as oxidative phosphorylation. Second, we observed morphological alterations in shape and area of specifically postsynaptic mitochondria in mGluR5 KO synapses using electron microscopy. Third, computational and biochemical assays suggested an increase of mitochondrial function in neurons, with increased level of NADP/H and oxidative damage in mGluR5 KO. Altogether, our observations provide diverse lines of evidence of the modulation of synaptic mitochondrial function by mGluR5. This connection suggests a role for mGluR5 as a mediator between synaptic activity and mitochondrial function, a finding which might be relevant for the improvement of the clinical potential of mGluR5.

【 授权许可】

Unknown