Abstract
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.
Highlights
The group 1 metabotropic glutamate receptor 5 is a G-protein coupled receptor expressed widely across the brain, predominantly in hippocampus, striatum and cortex [1]
We investigated synapse adaptation to loss or impaired metabotropic glutamate receptor 5 (mGluR5) function from a proteomic perspective
By using a mGluR5 KO mouse model, we first assessed the adaptation of synaptic proteins to the chronic lack of mGluR5 function throughout development and lifespan
Summary
The group 1 metabotropic glutamate receptor 5 (mGluR5) is a G-protein coupled receptor expressed widely across the brain, predominantly in hippocampus, striatum and cortex [1]. MGluR5 is an essential postsynaptic modulator of synaptic plasticity [6,7], facilitating the induction and persistence of long-term potentiation (LTP) and mediating long-term depression (LTD) [2,8,9] This type of LTD requires the synthesis of new proteins, a process regulated by mGluR5 at multiple levels [10]. The coordinated action of multiple second messengers [such as inositol triphosphate (IP3), Ca2+ and mitochondrial reactive oxygen species (ROS) [15]], protein kinases (e.g., PKC, MAPK, mTOR and ERK1/2) and scaffold protein interactions [16] comprises the cascades underlying mGluR5 functions This complicated signaling system leads to the regulation of diverse downstream processes and illustrates the extensive role of mGluR5 in synaptic function at different levels. MGluR5-mediated production of IP3 can lead to the generation of mitochondrial ROS, which activate ERK and PKA to increase neuronal excitability [15]
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