Reduced mGluR5 Activity Modulates Mitochondrial Function

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.

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Long-term depression of naive synapses in adult hippocampus induced by asynchronous synaptic activity

Journal of Neurophysiology ◽

10.1152/jn.1995.73.6.2596 ◽

1995 ◽

Vol 73 (6) ◽

pp. 2596-2601 ◽

Cited By ~ 21

Author(s):

S. Otani ◽

J. A. Connor

Keyword(s):

Receptor Antagonist ◽

Metabotropic Glutamate Receptor ◽

Hippocampal Slices ◽

Synaptic Activity ◽

Synthesis Inhibitor ◽

Long Term Depression ◽

Metabotropic Glutamate ◽

Adult Rat ◽

Adult Hippocampus

1. Two independent Schaffer collateral pathways converging to the same pyramidal cell were alternately stimulated by 2-Hz trains (900 pulses) offset by a 150-ms interval in adult rat hippocampal slices. The second input underwent an immediate and persistent long-term depression (LTD). Depression in the first input was smaller than the second input. A narrower interpulse interval (20 ms) failed to induce LTD in either input. 2. Neither the N-methyl-D-aspartate receptor antagonist DL-2-amino-5-phosphonovaleric acid nor the metabotropic glutamate receptor antagonist (+)-alpha-methyl-4-carboxylphenyl-glycine blocked this associative LTD. However, coapplication of these two antagonists blocked LTD. 3. Associative LTD was blocked by prior injection of the Ca2+ chelator bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid into the postsynaptic cell and by bath-applied L-NG-nitroarginine, a nitric oxide synthesis inhibitor. 4. We propose that temporally confined, asynchronous synaptic activity weakens the efficacy of naive synapses in slices from the adult hippocampus.

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Role of a metabotropic glutamate receptor in synaptic modulation in the accessory olfactory bulb

Nature ◽

10.1038/366687a0 ◽

1993 ◽

Vol 366 (6456) ◽

pp. 687-690 ◽

Cited By ~ 257

Author(s):

Yasunori Hayashi ◽

Akiko Momiyama ◽

Tomoyuki Takahashi ◽

Hitoshi Ohishi ◽

Reiko Ogawa-Meguro ◽

...

Keyword(s):

Olfactory Bulb ◽

Glutamate Receptor ◽

Metabotropic Glutamate Receptor ◽

Accessory Olfactory Bulb ◽

Synaptic Modulation ◽

Metabotropic Glutamate

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Distinct mechanisms underlie the subsynaptic mobility of presynaptic metabotropic glutamate receptor types to tune receptor activation

10.1101/2020.07.06.188995 ◽

2020 ◽

Author(s):

Anna Bodzęta ◽

Florian Berger ◽

Harold D. MacGillavry

Keyword(s):

Synaptic Transmission ◽

Active Zone ◽

Metabotropic Glutamate Receptors ◽

Molecular Mechanisms ◽

Metabotropic Glutamate Receptor ◽

Receptor Activation ◽

Synaptic Activity ◽

Control Surface ◽

Metabotropic Glutamate ◽

Surface Mobility

ABSTRACTPresynaptic metabotropic glutamate receptors (mGluRs) are essential for activity-dependent modulation of synaptic transmission in the brain. However, the mechanisms that control the subsynaptic distribution and mobility of these receptors to contribute to their function are poorly understood. Here, using super-resolution microscopy and single-molecule tracking, we provide novel insights in the molecular mechanisms that control the spatial distribution and mobility of presynaptic mGluRs. We demonstrate that mGluR2 localizes diffusely along the axon and boutons and is highly mobile, while mGluR7 is immobilized specifically at the active zone, indicating that distinct mechanisms underlie the dynamic distribution of these receptor types. Indeed, we found that the positioning of mGluR2 is modulated by intracellular interactions. In contrast, immobilization of mGluR7 at the active zone is mediated by its extracellular domain that interacts in trans with the postsynaptic adhesion molecule ELFN2. Moreover, we found that receptor activation or changing synaptic activity does not alter the surface mobility of presynaptic mGluRs. Additionally, computational modeling of presynaptic mGluRs activity revealed that the precise subsynaptic localization of mGluRs determines their activation probability and thus directly impacts their ability to modulate neurotransmitter release. Altogether, this study demonstrates that distinct mechanisms control surface mobility of presynaptic mGluRs to differentially contribute to the regulation of glutamatergic synaptic transmission.

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Regulation of neuron-specific gene transcription by stress hormone signalling requires synaptic activity in zebrafish

10.1101/714873 ◽

2019 ◽

Author(s):

Helen Eachus ◽

Dheemanth Subramanya ◽

Harriet E. Jackson ◽

Guannyu Wang ◽

Kieran Berntsen ◽

...

Keyword(s):

Glutamate Receptor ◽

Metabotropic Glutamate Receptor ◽

Receptor Gene ◽

Model Organism ◽

Receptor Expression ◽

Synaptic Activity ◽

Specific Gene ◽

Metabotropic Glutamate ◽

Synaptic Neurotransmission ◽

The Brain

AbstractThe Glucocorticoid Receptor (GR) co-ordinates metabolic and behavioural responses to stressors. We hypothesised that GR influences behaviour by modulating specific epigenetic and transcriptional processes in the brain. Using the zebrafish as a model organism, the brain methylomes of wild-type and grs357 mutant adults were analysed and GR-sensitive, differentially methylated regions (GR-DMRs) were identified. Two genes with GR-DMRs exhibited distinct methylation and transcriptional sensitivities to GR: the widely expressed direct GR target fkbp5 and neuron-specific aplp1. In larvae, neural activity is required for GR-mediated transcription of aplp1, but not for that of fkbp5. GR regulates metabotropic glutamate receptor gene expression, the activities of which also modulated aplp1 expression, implicating synaptic neurotransmission as an effector of GR function upstream of aplp1. Our results identify two distinct routes of GR-regulated transcription in the brain, including a pathway through which GR couples endocrine signalling to synaptic activity-regulated transcription by modulating metabotropic glutamate receptor expression.

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Inhibiting the LPS-induced enhancement of mEPSC frequency in superficial dorsal horn neurons may serve as an electrophysiological model for alleviating pain

Scientific Reports ◽

10.1038/s41598-019-52405-0 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Chin-Tsang Yang ◽

Shih-Ya Hung ◽

Sheng-Feng Hsu ◽

Iona MacDonald ◽

Jaung-Geng Lin ◽

...

Keyword(s):

Dorsal Horn ◽

Microglial Activation ◽

Metabotropic Glutamate Receptor ◽

Glutamate Release ◽

Synaptic Activity ◽

Superficial Dorsal Horn ◽

Nociceptive Transmission ◽

Metabotropic Glutamate ◽

Analgesic Effects ◽

Mepsc Frequency

Abstract Pain is a major primary health care problem. Emerging studies show that inhibition of spinal microglial activation reduces pain. However, the precise mechanisms by which microglial activation contributes to nociceptive synaptic transmission remain unclear. In this study, we measured spontaneous synaptic activity of miniature excitatory postsynaptic currents (mEPSCs) in rat spinal cord superficial dorsal horn (SDH, laminae I and II) neurons. Lipopolysaccharide (LPS) and adenosine triphosphate (ATP) increased the frequency, but not amplitude, of mEPSCs in SDH neurons. Microglial inhibitors minocycline and paeonol, as well as an astrocyte inhibitor, a P2Y1 receptor (P2Y1R) antagonist, and a metabotropic glutamate receptor 5 (mGluR5) antagonist, all prevented LPS-induced enhancement of mEPSC frequency. In mouse behavioral testing, minocycline and paeonol effectively reduced acetic acid-induced writhing and LPS-induced hyperalgesia. These results indicate that LPS-activated microglia release ATP, which stimulates astrocyte P2Y1Rs to release glutamate, triggering presynaptic mGluR5 receptors and increasing presynaptic glutamate release, leading to an increase in mEPSC frequency and enhancement of nociceptive transmission in SDH neurons. We propose that these effects can serve as a new electrophysiological model for evaluating pain. Moreover, we predict that pharmacologic agents capable of inhibiting the LPS-induced enhancement of mEPSC frequency in SDH neurons will have analgesic effects.

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Astrocytes drive cortical vasodilatory signaling by activating endothelial NMDA receptors

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x17734100 ◽

2017 ◽

Vol 39 (3) ◽

pp. 481-496 ◽

Cited By ~ 12

Author(s):

Lingling Lu ◽

Adam D Hogan-Cann ◽

Andrea K Globa ◽

Ping Lu ◽

James I Nagy ◽

...

Keyword(s):

Nitric Oxide ◽

Endothelial Cells ◽

Nmda Receptor ◽

Nmda Receptors ◽

Metabotropic Glutamate Receptor ◽

Flash Photolysis ◽

Basolateral Membrane ◽

Synaptic Activity ◽

Metabotropic Glutamate ◽

Signaling Axis

Astrocytes express neurotransmitter receptors that serve as sensors of synaptic activity and initiate signals leading to activity-dependent local vasodilation and increases in blood flow. We previously showed that arteriolar vasodilation produced by activation of cortical astrocytes is dependent on endothelial nitric oxide synthase (eNOS) and endogenous agonists of N-methyl-D-aspartate (NMDA) receptors. Here, we tested the hypothesis that these effects are mediated by NMDA receptors expressed by brain endothelial cells. Primary endothelial cultures expressed NMDA receptor subunits and produced nitric oxide in response to co-agonists, glutamate and D-serine. In cerebral cortex in situ, immunoelectron microscopy revealed that endothelial cells express the GluN1 NMDA receptor subunit at basolateral membrane surfaces in an orientation suitable for receiving intercellular messengers from brain cells. In cortical slices, activation of astrocytes by two-photon flash photolysis of a caged Ca2+ compound or application of a metabotropic glutamate receptor agonist caused endothelial NO generation and local vasodilation. These effects were mitigated by NMDA receptor antagonists and conditional gene silencing of endothelial GluN1, indicating at least partial dependence on endothelial NMDA receptors. Our observations identify a novel astrocyte-endothelial vasodilatory signaling axis that could contribute to endothelium-dependent vasodilation in brain functional hyperemia.

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