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Rabbit Anti-Metabotropic Glutamate Receptor 5 (mGluR5) , Unconjugated antibody

RRID:AB_2295173

Antibody ID

AB_2295173

Target Antigen

Metabotropic Glutamate Receptor 5 (mGluR5) rat

Proper Citation

(Millipore Cat# AB5675, RRID:AB_2295173)

Clonality

polyclonal antibody

Comments

seller recommendations: Immunohistochemistry; Western Blot; Western Blotting, Immunohistochemistry; Recommended Replacement for: AB1596, 06-451

Host Organism

rabbit

Vendor

Millipore

Heterogeneity of Cell Surface Glutamate and GABA Receptor Expression in Shank and CNTN4 Autism Mouse Models.

  • Heise C
  • Front Mol Neurosci
  • 2018 Jul 5

Literature context:


Abstract:

Autism spectrum disorder (ASD) refers to a large set of neurodevelopmental disorders, which have in common both repetitive behavior and abnormalities in social interactions and communication. Interestingly, most forms of ASD have a strong genetic contribution. However, the molecular underpinnings of this disorder remain elusive. The SHANK3 gene (and to a lesser degree SHANK2) which encode for the postsynaptic density (PSD) proteins SHANK3/SHANK2 and the CONTACTIN 4 gene which encodes for the neuronal glycoprotein CONTACTIN4 (CNTN4) exhibit mutated variants which are associated with ASD. Like many of the other genes associated with ASD, both SHANKs and CNTN4 affect synapse formation and function and are therefore related to the proper development and signaling capability of excitatory and inhibitory neuronal networks in the adult mammal brain. In this study, we used mutant/knock-out mice of Shank2 (Shank2-/-), Shank3 (Shank3αβ-/-), and Cntn4 (Cntn4-/-) as ASD-models to explore whether these mice share a molecular signature in glutamatergic and GABAergic synaptic transmission in ASD-related brain regions. Using a biotinylation assay and subsequent western blotting we focused our analysis on cell surface expression of several ionotropic glutamate and GABA receptor subunits: GluA1, GluA2, and GluN1 were analyzed for excitatory synaptic transmission, and the α1 subunit of the GABAA receptor was analyzed for inhibitory synaptic transmission. We found that both Shank2-/- and Shank3αβ-/- mice exhibit reduced levels of several cell surface glutamate receptors in the analyzed brain regions-especially in the striatum and thalamus-when compared to wildtype controls. Interestingly, even though Cntn4-/- mice also show reduced levels of some cell surface glutamate receptors in the cortex and hippocampus, increased levels of cell surface glutamate receptors were found in the striatum. Moreover, Cntn4-/- mice do not only show brain region-specific alterations in cell surface glutamate receptors but also a downregulation of cell surface GABA receptors in several of the analyzed brain regions. The results of this study suggest that even though mutations in defined genes can be associated with ASD this does not necessarily result in a common molecular phenotype in surface expression of glutamatergic and GABAergic receptor subunits in defined brain regions.

Funding information:
  • Howard Hughes Medical Institute - AG010770-18A1(United States)

The Temporal Dynamics of Arc Expression Regulate Cognitive Flexibility.

  • Wall MJ
  • Neuron
  • 2018 Jun 27

Literature context:


Abstract:

Neuronal activity regulates the transcription and translation of the immediate-early gene Arc/Arg3.1, a key mediator of synaptic plasticity. Proteasome-dependent degradation of Arc tightly limits its temporal expression, yet the significance of this regulation remains unknown. We disrupted the temporal control of Arc degradation by creating an Arc knockin mouse (ArcKR) where the predominant Arc ubiquitination sites were mutated. ArcKR mice had intact spatial learning but showed specific deficits in selecting an optimal strategy during reversal learning. This cognitive inflexibility was coupled to changes in Arc mRNA and protein expression resulting in a reduced threshold to induce mGluR-LTD and enhanced mGluR-LTD amplitude. These findings show that the abnormal persistence of Arc protein limits the dynamic range of Arc signaling pathways specifically during reversal learning. Our work illuminates how the precise temporal control of activity-dependent molecules, such as Arc, regulates synaptic plasticity and is crucial for cognition.

Funding information:
  • NICHD NIH HHS - R21 HD065269(United States)
  • NIGMS NIH HHS - R25 GM109442()
  • NINDS NIH HHS - R00 NS076364()
  • NINDS NIH HHS - R01 NS085093()

Alterations in mGlu5 receptor expression and function in the striatum in a rat depression model.

  • Mao LM
  • J. Neurochem.
  • 2018 Jan 18

Literature context:


Abstract:

Major depressive disorder is a common form of mental illness. Many brain regions are implicated in the pathophysiology and symptomatology of depression. Among key brain areas is the striatum that controls reward and mood and is involved in the development of core depression-like behavior in animal models of depression. While molecular mechanisms in this region underlying depression-related behavior are poorly understood, the glutamatergic input to the striatum is believed to play a role. In this study, we investigated changes in metabotropic glutamate (mGlu) receptor expression and signaling in the striatum of adult rats in response to prolonged (10-12 weeks) social isolation, a pre-validated animal paradigm modeling depression in adulthood. We found that mGlu5 receptor protein levels in the striatum were increased in rats that showed typical depression- and anxiety-like behavior after chronic social isolation. This increase in mGlu5 receptor expression was seen in both subdivisions of the striatum, the nucleus accumbens and caudate putamen. At subcellular and subsynaptic levels, mGlu5 receptor expression was elevated in surface membranes at synaptic sites. In striatal neurons, the mGlu5-associated phosphoinositide signaling pathway was augmented in its efficacy after prolonged social isolation. These data indicate that the mGlu5 receptor is a sensitive substrate of depression. Adulthood social isolation leads to the up-regulation of mGlu5 receptor expression and function in striatal neurons.

Funding information:
  • NIDA NIH HHS - R01 DA010355()
  • NIGMS NIH HHS - GM57089(United States)
  • NIMH NIH HHS - R01 MH061469()

Protein kinase Cɛ activity regulates mGluR5 surface expression in the rat nucleus accumbens.

  • Schwendt M
  • J. Neurosci. Res.
  • 2017 Nov 16

Literature context:


Abstract:

Type 5 metabotropic glutamate receptors (mGluR5) activate protein kinase C (PKC) via coupling to Gαq/11 protein signaling. We have previously demonstrated that the epsilon isoform of PKC (PKCɛ) is a critical downstream target of mGluR5 in regulating behavioral and biochemical responses to alcohol. Recent evidence suggests that PKC-mediated phosphorylation of mGluR5 can lead to receptor desensitization and internalization. We therefore sought to examine the specific involvement of PKCɛ in the regulation of mGluR5 surface expression in the nucleus accumbens (NAc), a key regulator of alcohol-associated behaviors. Coronal brain sections from male Wistar rats were analyzed for either colocalization of mGluR5 and PKCɛ via immunohistochemistry or changes in mGluR5 surface expression and PKCɛ phosphorylation following local application of PKCɛ translocation activator or inhibitor peptides and/or an orthosteric mGluR5 agonist. We observed colocalization of mGluR5 and PKCɛ in the NAc. We also showed that intra-NAc infusion of the PKCɛ translocation inhibitor ɛV1-2 increased mGluR5 surface expression under baseline conditions. Stimulation of mGluR5 with an orthosteric agonist DHPG, dose dependently increased ERK1/2 and PKCɛ phosphorylation as well as mGluR5 internalization in acute NAc slices. Finally, we observed that activation of PKCɛ translocation with Tat-ΨɛRACK peptide mediates agonist-independent mGluR5 internalization, whereas PKCɛ translocation inhibitor ɛV1-2 prevents agonist-dependent internalization of mGluR5 in NAc slice preparations. These findings suggest that the subcellular localization of mGluR5 in the NAc is regulated by PKCɛ under basal and stimulation conditions, which may influence the role of mGluR5-PKCɛ signaling in alcohol-related behaviors. © 2016 Wiley Periodicals, Inc.

Pharmacological enhancement of mGlu5 receptors rescues behavioral deficits in SHANK3 knock-out mice.

  • Vicidomini C
  • Mol. Psychiatry
  • 2017 Jun 29

Literature context:


Abstract:

SHANK3 (also called PROSAP2) genetic haploinsufficiency is thought to be the major cause of neuropsychiatric symptoms in Phelan-McDermid syndrome (PMS). PMS is a rare genetic disorder that causes a severe form of intellectual disability (ID), expressive language delays and other autistic features. Furthermore, a significant number of SHANK3 mutations have been identified in patients with autism spectrum disorders (ASD), and SHANK3 truncating mutations are associated with moderate to profound ID. The Shank3 protein is a scaffold protein that is located in the postsynaptic density (PSD) of excitatory synapses and is crucial for synapse development and plasticity. In this study, we investigated the molecular mechanisms associated with the ASD-like behaviors observed in Shank3Δ11-/- mice, in which exon 11 has been deleted. Our results indicate that Shank3 is essential to mediating metabotropic glutamate receptor 5 (mGlu5)-receptor signaling by recruiting Homer1b/c to the PSD, specifically in the striatum and cortex. Moreover, augmenting mGlu5-receptor activity by administering 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide ameliorated the functional and behavioral defects that were observed in Shank3Δ11-/- mice, suggesting that pharmaceutical treatments that increase mGlu5 activity may represent a new approach for treating patients that are affected by PMS and SHANK3 mutations.

Funding information:
  • Wellcome Trust - WT098418MA(United Kingdom)

Intracellular mGluR5 plays a critical role in neuropathic pain.

  • Vincent K
  • Nat Commun
  • 2016 Feb 3

Literature context:


Abstract:

Spinal mGluR5 is a key mediator of neuroplasticity underlying persistent pain. Although brain mGluR5 is localized on cell surface and intracellular membranes, neither the presence nor physiological role of spinal intracellular mGluR5 is established. Here we show that in spinal dorsal horn neurons >80% of mGluR5 is intracellular, of which ∼60% is located on nuclear membranes, where activation leads to sustained Ca(2+) responses. Nerve injury inducing nociceptive hypersensitivity also increases the expression of nuclear mGluR5 and receptor-mediated phosphorylated-ERK1/2, Arc/Arg3.1 and c-fos. Spinal blockade of intracellular mGluR5 reduces neuropathic pain behaviours and signalling molecules, whereas blockade of cell-surface mGluR5 has little effect. Decreasing intracellular glutamate via blocking EAAT-3, mimics the effects of intracellular mGluR5 antagonism. These findings show a direct link between an intracellular GPCR and behavioural expression in vivo. Blockade of intracellular mGluR5 represents a new strategy for the development of effective therapies for persistent pain.

Funding information:
  • Canadian Institutes of Health Research - MOP-119279()
  • Canadian Institutes of Health Research - MOP-53246()
  • NICHD NIH HHS - U54 HD087011()
  • NIDDK NIH HHS - R01 DK072246(United States)
  • NINDS NIH HHS - NS081454()

Protein kinase A directly phosphorylates metabotropic glutamate receptor 5 to modulate its function.

  • Uematsu K
  • J. Neurochem.
  • 2015 Mar 13

Literature context:


Abstract:

Metabotropic glutamate receptor 5 (mGluR5) regulates excitatory post-synaptic signaling in the central nervous system (CNS) and is implicated in various CNS disorders. Protein kinase A (PKA) signaling is known to play a critical role in neuropsychiatric disorders such as Parkinson's disease, schizophrenia, and addiction. Dopamine signaling is known to modulate the properties of mGluR5 in a cAMP- and PKA-dependent manner, suggesting that mGluR5 may be a direct target for PKA. Our study identifies mGluR5 at Ser870 as a direct substrate for PKA phosphorylation and demonstrates that this phosphorylation plays a critical role in the PKA-mediated modulation of mGluR5 functions such as extracellular signal-regulated kinase phosphorylation and intracellular Ca(2+) oscillations. The identification of the molecular mechanism by which PKA signaling modulates mGluR5-mediated cellular responses contributes to the understanding of the interaction between dopaminergic and glutamatergic neuronal signaling. We identified serine residue 870 (S870) in metabotropic glutamate receptor 5 (mGluR5) as a direct substrate for protein kinase A (PKA). The phosphorylation of this site regulates the ability of mGluR5 to induce extracellular signal-regulated kinase (ERK) phosphorylation and intracellular Ca(2+) oscillations. This study provides a direct molecular mechanism by which PKA signaling interacts with glutamate neurotransmission.

Early-life-stress affects the homeostasis of glutamatergic synapses.

  • Toya S
  • Eur. J. Neurosci.
  • 2014 Dec 9

Literature context:


Abstract:

Early-life stress induces several neuropsychological disorders in adulthood, including depression. Such disorders may be induced by functional alteration of the glutamatergic system. However, their underlying mechanisms have not yet been fully clarified. Furthermore, the involvement of glucocorticoids, which are representative stress hormones, has not yet been fully clarified. In this study, we used maternal deprivation (MD) mice as an early-life-stress model, and studied the changes in the glutamatergic system in adulthood. The glutamate concentration and neuronal activity in the somatosensory cortex (SSC) increased under basal conditions in MD mice. Stressful physical stimulation (SPS) increased the concentration of corticosterone, but not of glutamate, in the control mouse SSC. On the other hand, in the MD mice, although the basal concentration of corticosterone in the SSC increased, no SPS-induced increase was observed. In contrast, the concentration of glutamate increased greatly during SPS. It was significantly high for 30 min after stimulation. The expression level of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/N-methyl-d-aspartate receptors in the MD mice was also changed compared with that in the control mice after stimulation. These findings indicate that early-life stress disrupts the homeostasis of glutamatergic synapses.

Funding information:
  • NIAMS NIH HHS - R01 AR043510(United States)
  • NIDCD NIH HHS - R01 DC009405(United States)

Adenosine A2A receptor in the monkey basal ganglia: ultrastructural localization and colocalization with the metabotropic glutamate receptor 5 in the striatum.

  • Bogenpohl JW
  • J. Comp. Neurol.
  • 2012 Feb 15

Literature context:


Abstract:

The adenosine A(2A) receptor (A(2A) R) is a potential drug target for the treatment of Parkinson's disease and other neurological disorders. In rodents, the therapeutic efficacy of A(2A) R modulation is improved by concomitant modulation of the metabotropic glutamate receptor 5 (mGluR5). To elucidate the anatomical substrate(s) through which these therapeutic benefits could be mediated, pre-embedding electron microscopy immunohistochemistry was used to conduct a detailed, quantitative ultrastructural analysis of A(2A) R localization in the primate basal ganglia and to assess the degree of A(2A) R/mGluR5 colocalization in the striatum. A(2A) R immunoreactivity was found at the highest levels in the striatum and external globus pallidus (GPe). However, the monkey, but not the rat, substantia nigra pars reticulata (SNr) also harbored a significant level of neuropil A(2A) R immunoreactivity. At the electron microscopic level, striatal A(2A) R labeling was most commonly localized in postsynaptic elements (58% ± 3% of labeled elements), whereas, in the GPe and SNr, the labeling was mainly presynaptic (71% ± 5%) or glial (27% ± 6%). In both striatal and pallidal structures, putative inhibitory and excitatory terminals displayed A(2A) R immunoreactivity. Striatal A(2A) R/mGluR5 colocalization was commonly found; 60-70% of A(2A) R-immunoreactive dendrites or spines in the monkey striatum coexpress mGluR5. These findings provide the first detailed account of the ultrastructural localization of A(2A) R in the primate basal ganglia and demonstrate that A(2A) R and mGluR5 are located to interact functionally in dendrites and spines of striatal neurons. Together, these data foster a deeper understanding of the substrates through which A(2A) R could regulate primate basal ganglia function and potentially mediate its therapeutic effects in parkinsonism.

Funding information:
  • Wellcome Trust - WT098418MA(United Kingdom)

mGluR5 in cortical excitatory neurons exerts both cell-autonomous and -nonautonomous influences on cortical somatosensory circuit formation.

  • Ballester-Rosado CJ
  • J. Neurosci.
  • 2010 Dec 15

Literature context:


Abstract:

Glutamatergic neurotransmission plays important roles in sensory map formation. The absence of the group I metabotropic glutamate receptor 5 (mGluR5) leads to abnormal sensory map formation throughout the mouse somatosensory pathway. To examine the role of cortical mGluR5 expression on barrel map formation, we generated cortex-specific mGluR5 knock-out (KO) mice. Eliminating mGluR5 function solely in cortical excitatory neurons affects, not only the whisker-related organization of cortical neurons (barrels), but also the patterning of their presynaptic partners, the thalamocortical axons (TCAs). In contrast, subcortical whisker maps develop normally in cortical-mGluR5 KO mice. In the S1 cortex of cortical-mGluR5 KO, layer IV neurons are homogenously distributed and have no clear relationship to the location of TCA clusters. The altered dendritic morphology of cortical layer IV spiny stellate neurons in cortical-mGluR5 KO mice argues for a cell-autonomous role of mGluR5 in dendritic patterning. Furthermore, morphometric analysis of single TCAs in both cortical- and global-mGluR5 KO mice demonstrated that in these mice, the complexity of axonal arbors is reduced, while the area covered by TCA arbors is enlarged. Using voltage-clamp whole-cell recordings in acute thalamocortical brain slices, we found that KO of mGluR5 from cortical excitatory neurons reduced inhibitory but not excitatory inputs onto layer IV neurons. This suggests that mGluR5 signaling in cortical excitatory neurons nonautonomously modulates the functional development of GABAergic circuits. Together, our data provide strong evidence that mGluR5 signaling in cortical principal neurons exerts both cell-autonomous and -nonautonomous influences to modulate the formation of cortical sensory circuits.

Funding information:
  • Intramural NIH HHS - (United States)

Ultrastructural relationships between cortical, thalamic, and amygdala glutamatergic inputs and group I metabotropic glutamate receptors in the rat accumbens.

  • Mitrano DA
  • J. Comp. Neurol.
  • 2010 Apr 15

Literature context:


Abstract:

Changes in glutamatergic transmission in the nucleus accumbens play a key role in mediating reward-related behaviors and addiction to psychostimulants. Glutamatergic inputs to the accumbens originate from multiple sources, including the prefrontal cortex, basolateral amygdala, and midline thalamus. The group I metabotropic glutamate receptors (mGluRs) are found throughout the core and shell of the nucleus accumbens, but their localization and function at specific glutamatergic synapses remain unknown. To further characterize the substrate that underlies group I mGluR functions in the accumbens, we combined anterograde tract tracing method with electron microscopy immunocytochemistry to study the ultrastructural relationships between specific glutamatergic afferents and mGluR1a- or mGluR5-containing neurons in the rat nucleus accumbens. Although cortical, thalamic, and amygdala glutamatergic terminals contact both mGluR1a- and mGluR5-immunoreactive dendrites and spines in the shell and core of the accumbens, they do so to varying degrees. Overall, glutamatergic terminals contact mGluR1a-positive spines about 30% of the time, whereas they form synapses twice as frequently with mGluR5-labeled spines. At the subsynaptic level, mGluR5 is more frequently expressed perisynaptically and closer to the edges of glutamatergic axospinous synapses than mGluR1a, suggesting a differential degree of activation of the two group I mGluRs by transmitter spillover from glutamatergic synapses in the rat accumbens. These results lay the foundation for a deeper understanding of group I mGluR-mediated effects in the ventral striatum, and their potential therapeutic benefits in drug addiction and other neuropsychiatric changes in reward-related behaviors.

Differential role for synaptojanin 1 in rod and cone photoreceptors.

  • Holzhausen LC
  • J. Comp. Neurol.
  • 2009 Dec 10

Literature context:


Abstract:

Synaptojanin 1 (SynJ1) is a polyphosphoinositide phosphatase involved in clathrin-mediated endocytosis in conventional synapses. Studies with the zebrafish mutant nrc have revealed that loss of SynJ1 also affects cone photoreceptor ribbon synapses, causing pronounced morphological and functional abnormalities. In this study we continue to examine the role of SynJ1 in photoreceptors. Using a newly generated antibody specific for zebrafish SynJ1, we localized this protein predominantly to cone photoreceptors. We then used blastula stage transplantation experiments to demonstrate that rods from nrc mutants lacking SynJ1 develop normally and do not have the pronounced morphological defects detected in cones. Given the known involvement of SynJ1 in synaptic vesicle endocytosis, we hypothesize that rods and cones use distinct mechanisms for vesicle recycling.

Comparative analysis of the subcellular and subsynaptic localization of mGluR1a and mGluR5 metabotropic glutamate receptors in the shell and core of the nucleus accumbens in rat and monkey.

  • Mitrano DA
  • J. Comp. Neurol.
  • 2007 Feb 1

Literature context:


Abstract:

Group I metabotropic glutamate receptors (mGluRs) play critical roles in synaptic plasticity and drug addiction. To characterize potential sites whereby these receptors mediate their effects in the ventral striatum, we studied the subcellular and subsynaptic localization of mGluR1a and mGluR5 in the shell and core of the nucleus accumbens in rat and monkey. In both species, group I mGluRs are mainly postsynaptic in dendrites and spines, with rare presynaptic labeling in unmyelinated axons. Minor, yet significant, differences in proportions of specific immunoreactive elements were found between the accumbens shell and the accumbens core in monkey. At the subsynaptic level, significant differences were found in the proportion of plasma membrane-bound mGluR5 labeling between species. In dendrites, spines, and unmyelinated axons, a significantly larger proportion of mGluR5 labeling was bound to the plasma membrane in rats (50-70%) than in monkeys (30-50%). Conversely, mGluR1a displayed the same pattern of immunogold labeling in the two species. Electron microscopic colocalization studies revealed 30% colocalization of mGluR1a and mGluR5 in dendrites and as much as 50-65% in spines in both compartments of the rat accumbens. Both group I mGluRs were significantly expressed in D1-immunoreactive dendritic processes (60-75% colocalization) and spines (30-50%) of striatal projection neurons as well as dendrites of cholinergic (30-70%) and parvalbumin-containing (70-85%) interneurons. These findings highlight the widespread expression of group I mGluRs in projection neurons and interneurons of the shell and core of the nucleus accumbens, providing a solid foundation for regulatory and therapeutic functions of group I mGluRs in reward-related behaviors and drug addiction.

Funding information:
  • NCRR NIH HHS - P20 RR016476(United States)