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19 pages, 2894 KiB

Open AccessFeature PaperArticle

Protein Networks Associated with Native Metabotropic Glutamate 1 Receptors (mGlu₁) in the Mouse Cerebellum

by Mahnaz Mansouri, Leopold Kremser, Thanh-Phuong Nguyen, Yu Kasugai, Laura Caberlotto, Martin Gassmann, Bettina Sarg, Herbert Lindner, Bernhard Bettler, Lucia Carboni and Francesco Ferraguti

Cells 2023, 12(9), 1325; https://doi.org/10.3390/cells12091325 - 5 May 2023

Viewed by 2362

Abstract

The metabotropic glutamate receptor 1 (mGlu₁) plays a pivotal role in synaptic transmission and neuronal plasticity. Despite the fact that several interacting proteins involved in the mGlu₁ subcellular trafficking and intracellular transduction mechanisms have been identified, the protein network associated [...] Read more.

The metabotropic glutamate receptor 1 (mGlu₁) plays a pivotal role in synaptic transmission and neuronal plasticity. Despite the fact that several interacting proteins involved in the mGlu₁ subcellular trafficking and intracellular transduction mechanisms have been identified, the protein network associated with this receptor in specific brain areas remains largely unknown. To identify novel mGlu₁-associated protein complexes in the mouse cerebellum, we used an unbiased tissue-specific proteomic approach, namely co-immunoprecipitation followed by liquid chromatography/tandem mass spectrometry analysis. Many well-known protein complexes as well as novel interactors were identified, including G-proteins, Homer, δ2 glutamate receptor, 14-3-3 proteins, and Na/K-ATPases. A novel putative interactor, KCTD12, was further investigated. Reverse co-immunoprecipitation with anti-KCTD12 antibodies revealed mGlu₁ in wild-type but not in KCTD12-knock-out homogenates. Freeze-fracture replica immunogold labeling co-localization experiments showed that KCTD12 and mGlu₁ are present in the same nanodomain in Purkinje cell spines, although at a distance that suggests that this interaction is mediated through interposed proteins. Consistently, mGlu₁ could not be co-immunoprecipitated with KCTD12 from a recombinant mammalian cell line co-expressing the two proteins. The possibility that this interaction was mediated via GABA_B receptors was excluded by showing that mGlu₁ and KCTD12 still co-immunoprecipitated from GABA_B receptor knock-out tissue. In conclusion, this study identifies tissue-specific mGlu₁-associated protein clusters including KCTD12 at Purkinje cell synapses. Full article

(This article belongs to the Special Issue The Role of Metabotropic Glutamate Receptors in Health and Disease)

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17 pages, 2020 KiB

Open AccessArticle

Effect of the Metabotropic Glutamate Receptor Type 5 Negative Allosteric Modulator Dipraglurant on Motor and Non-Motor Symptoms of Parkinson’s Disease

by Mark P. Epping-Jordan, Françoise Girard, Anne-Sophie Bessis, Vincent Mutel, Christelle Boléa, Francis Derouet, Abdelhak Bessif, Brice Mingard, Stéphanie Barbier, Justine S. Paradis, Jean-Philippe Rocher, Robert Lütjens, Mikhail Kalinichev and Sonia Poli

Cells 2023, 12(7), 1004; https://doi.org/10.3390/cells12071004 - 24 Mar 2023

Cited by 3 | Viewed by 2706

Abstract

Parkinson’s disease (PD) patients suffer not only from the primary motor symptoms of the disease but also from a range of non-motor symptoms (NMS) that cause disability and low quality of life. Excessive glutamate activity in the basal ganglia resulting from degeneration of [...] Read more.

Parkinson’s disease (PD) patients suffer not only from the primary motor symptoms of the disease but also from a range of non-motor symptoms (NMS) that cause disability and low quality of life. Excessive glutamate activity in the basal ganglia resulting from degeneration of the nigrostriatal dopamine pathway has been implicated in the motor symptoms, NMS and dyskinesias in PD patients. In this study, we investigated the effects of a selective mGlu5 negative allosteric modulator (NAM), dipraglurant, in a rodent motor symptoms model of PD, but also in models of anxiety, depression and obsessive-compulsive disorder, all of which are among the most prevalent NMS symptoms. Dipraglurant is rapidly absorbed after oral administration, readily crosses the blood-brain barrier, and exhibits a high correlation between plasma concentration and efficacy in behavioral models. In vivo, dipraglurant dose-dependently reduced haloperidol-induced catalepsy, increased punished licks in the Vogel conflict-drinking model, decreased immobility time in the forced swim test, decreased the number of buried marbles in the marble-burying test, but had no effect on rotarod performance or locomotor activity. These findings suggest that dipraglurant may have benefits to address some of the highly problematic comorbid non-motor symptoms of PD, in addition to its antidyskinetic effect demonstrated in PD-LID patients. Full article

(This article belongs to the Special Issue The Role of Metabotropic Glutamate Receptors in Health and Disease)

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23 pages, 5309 KiB

Open AccessArticle

Oscillatory Deficits in the Sub-Chronic PCP Rat Model for Schizophrenia Are Reversed by mGlu5 Receptor-Positive Allosteric Modulators VU0409551 and VU0360172

by Jessica Brown, Ben Grayson, Joanna C. Neill, Michael Harte, Mark J. Wall and Richard T. Ngomba

Cells 2023, 12(6), 919; https://doi.org/10.3390/cells12060919 - 16 Mar 2023

Cited by 3 | Viewed by 2544

Abstract

The cognitive deficits of schizophrenia are linked to imbalanced excitatory and inhibitory signalling in the prefrontal cortex (PFC), disrupting gamma oscillations. We previously demonstrated that two mGlu5 receptor-positive allosteric modulators (PAMs), VU0409551 and VU0360172, restore cognitive deficits in the sub-chronic PCP (scPCP) rodent [...] Read more.

The cognitive deficits of schizophrenia are linked to imbalanced excitatory and inhibitory signalling in the prefrontal cortex (PFC), disrupting gamma oscillations. We previously demonstrated that two mGlu5 receptor-positive allosteric modulators (PAMs), VU0409551 and VU0360172, restore cognitive deficits in the sub-chronic PCP (scPCP) rodent model for schizophrenia via distinct changes in PFC intracellular signalling molecules. Here, we have assessed ex vivo gamma oscillatory activity in PFC slices from scPCP rats and investigated the effects of VU0409551 and VU0360172 upon oscillatory power. mGlu5 receptor, protein kinase C (PKC), and phospholipase C (PLC) inhibition were also used to examine ‘modulation bias’ in PAM activity. The amplitude and area power of gamma oscillations were significantly diminished in the scPCP model. Slice incubation with either VU0409551 or VU0360172 rescued scPCP-induced oscillatory deficits in a concentration-dependent manner. MTEP blocked the PAM-induced restoration of oscillatory power, confirming the requirement of mGlu5 receptor modulation. Whilst PLC inhibition prevented the power increase mediated by both PAMs, PKC inhibition diminished the effects of VU0360172 but not VU0409551. This aligns with previous reports that VU0409551 exhibits preferential activation of the phosphatidylinositol-3-kinase (PI3K) signalling pathway over the PKC cascade. Restoration of the excitatory/inhibitory signalling balance and gamma oscillations may therefore underlie the mGluR5 PAM-mediated correction of scPCP-induced cognitive deficits. Full article

(This article belongs to the Special Issue The Role of Metabotropic Glutamate Receptors in Health and Disease)

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17 pages, 4486 KiB

Open AccessArticle

Hodgkin Lymphoma Cell Lines and Tissues Express mGluR5: A Potential Link to Ophelia Syndrome and Paraneoplastic Neurological Disease

by Sofia Schnell, Ellen Knierim, Petra Bittigau, Jakob Kreye, Kathrin Hauptmann, Patrick Hundsdoerfer, Susanne Morales-Gonzalez, Markus Schuelke and Marc Nikolaus

Cells 2023, 12(4), 606; https://doi.org/10.3390/cells12040606 - 13 Feb 2023

Cited by 1 | Viewed by 2558

Abstract

Ophelia syndrome is characterized by the coincidence of severe neuropsychiatric symptoms, classical Hodgkin lymphoma, and the presence of antibodies to the metabotropic glutamate 5 receptor (mGluR5). Little is known about the pathogenetic link between these symptoms and the role that anti-mGluR5-antibodies play. We [...] Read more.

Ophelia syndrome is characterized by the coincidence of severe neuropsychiatric symptoms, classical Hodgkin lymphoma, and the presence of antibodies to the metabotropic glutamate 5 receptor (mGluR5). Little is known about the pathogenetic link between these symptoms and the role that anti-mGluR5-antibodies play. We investigated lymphoma tissue from patients with Ophelia syndrome and with isolated classical Hodgkin lymphoma by quantitative immunocytochemistry for mGluR5-expression. Further, we studied the L-1236, L-428, L-540, SUP-HD1, KM-H2, and HDLM-2 classical Hodgkin lymphoma cell lines by FACS and Western blot for mGluR5-expression, and by transcriptome analysis. mGluR5 surface expression differed significantly in terms of receptor density, distribution pattern, and percentage of positive cells. The highest expression levels were found in the L-1236 line. RNA-sequencing revealed more than 800 genes that were higher expressed in the L-1236 line in comparison to the other classical Hodgkin lymphoma cell lines. High mGluR5-expression was associated with upregulation of PI3K/AKT and MAPK pathways and of downstream targets (e.g., EGR1) known to be involved in classical Hodgkin lymphoma progression. Finally, mGluR5 expression was increased in the classical Hodgkin lymphoma-tissue of our Ophelia syndrome patient in contrast to five classical Hodgkin lymphoma-patients without autoimmune encephalitis. Given the association of encephalitis and classical Hodgkin lymphoma in Ophelia syndrome, it is possible that mGluR5-expression in classical Hodgkin lymphoma cells not only drives tumor progression but also triggers anti-mGluR5 encephalitis even before classical Hodgkin lymphoma becomes manifest. Full article

(This article belongs to the Special Issue The Role of Metabotropic Glutamate Receptors in Health and Disease)

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17 pages, 3324 KiB

Open AccessArticle

Targeting mGlu1 Receptors in the Treatment of Motor and Cognitive Dysfunctions in Mice Modeling Type 1 Spinocerebellar Ataxia

by Francesca Liberatore, Nico Antenucci, Daniel Tortolani, Giada Mascio, Federico Fanti, Manuel Sergi, Giuseppe Battaglia, Valeria Bruno, Ferdinando Nicoletti, Mauro Maccarrone and Serena Notartomaso

Cells 2022, 11(23), 3916; https://doi.org/10.3390/cells11233916 - 3 Dec 2022

Cited by 2 | Viewed by 2278

Abstract

Type 1 spinocerebellar ataxia (SCA1) is a progressive neurodegenerative disorder with no effective treatment to date. Using mice modeling SCA1, it has been demonstrated that a drug that amplifies mGlu1 receptor activation (mGlu1 receptor PAM, Ro0711401) improves motor coordination without the development of [...] Read more.

Type 1 spinocerebellar ataxia (SCA1) is a progressive neurodegenerative disorder with no effective treatment to date. Using mice modeling SCA1, it has been demonstrated that a drug that amplifies mGlu1 receptor activation (mGlu1 receptor PAM, Ro0711401) improves motor coordination without the development of tolerance when cerebellar dysfunction manifests (i.e., in 30-week-old heterozygous ataxin-1 [154Q/2Q] transgenic mice). SCA1 is also associated with cognitive dysfunction, which may precede cerebellar motor signs. Here, we report that otherwise healthy, 8-week-old SCA1 mice showed a defect in spatial learning and memory associated with reduced protein levels of mGlu1α receptors, the GluN2B subunit of NMDA receptors, and cannabinoid CB1 receptors in the hippocampus. Systemic treatment with Ro0711401 (10 mg/kg, s.c.) partially corrected the learning deficit in the Morris water maze and restored memory retention in the SCA1 mice model. This treatment also enhanced hippocampal levels of the endocannabinoid, anandamide, without changing the levels of 2-arachidonylglycerol. These findings suggest that mGlu1 receptor PAMs may be beneficial in the treatment of motor and nonmotor signs associated with SCA1 and encourage further studies in animal models of SCA1 and other types of SCAs. Full article

(This article belongs to the Special Issue The Role of Metabotropic Glutamate Receptors in Health and Disease)

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15 pages, 2581 KiB

Open AccessArticle

Control of Theta Oscillatory Activity Underlying Fear Expression by mGlu₅ Receptors

by Pawel Matulewicz, Arnau Ramos-Prats, Xavier Gómez-Santacana, Amadeu Llebaria and Francesco Ferraguti

Cells 2022, 11(22), 3555; https://doi.org/10.3390/cells11223555 - 10 Nov 2022

Cited by 2 | Viewed by 1997

Abstract

Metabotropic glutamate 5 receptors (mGlu₅) are thought to play an important role in mediating emotional information processing. In particular, negative allosteric modulators (NAMs) of mGlu₅ have received a lot of attention as potential novel treatments for several neuropsychiatric diseases, including [...] Read more.

Metabotropic glutamate 5 receptors (mGlu₅) are thought to play an important role in mediating emotional information processing. In particular, negative allosteric modulators (NAMs) of mGlu₅ have received a lot of attention as potential novel treatments for several neuropsychiatric diseases, including anxiety-related disorders. The aim of this study was to assess the influence of pre- and post-training mGlu₅ inactivation in cued fear conditioned mice on neuronal oscillatory activity during fear retrieval. For this study we used the recently developed mGlu₅ NAM Alloswicth-1 administered systemically. Injection of Alloswicth-1 before, but not after, fear conditioning resulted in a significant decrease in freezing upon fear retrieval. Mice injected with Alloswicth-1 pre-training were also implanted with recording microelectrodes into both the medial prefrontal cortex (mPFC) and ventral hippocampus (vHPC). The recordings revealed a reduction in theta rhythmic activity (4–12 Hz) in both the mPFC and vHPC during fear retrieval. These results indicate that inhibition of mGlu₅ signaling alters local oscillatory activity in principal components of the fear brain network underlying a reduced response to a predicted threat. Full article

(This article belongs to the Special Issue The Role of Metabotropic Glutamate Receptors in Health and Disease)

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16 pages, 1570 KiB

Open AccessArticle

Presynaptic 5-HT_2A-mGlu2/3 Receptor–Receptor Crosstalk in the Prefrontal Cortex: Metamodulation of Glutamate Exocytosis

by Alice Taddeucci, Guendalina Olivero, Alessandra Roggeri, Claudio Milanese, Francesco Paolo Di Giorgio, Massimo Grilli, Mario Marchi, Beatrice Garrone and Anna Pittaluga

Cells 2022, 11(19), 3035; https://doi.org/10.3390/cells11193035 - 28 Sep 2022

Cited by 7 | Viewed by 3352

Abstract

The glutamatergic nerve endings of a rat prefrontal cortex (PFc) possess presynaptic 5-HT_2A heteroreceptors and mGlu2/3 autoreceptors, whose activation inhibits glutamate exocytosis, and is measured as 15 mM KCl-evoked [³H]D-aspartate ([³H]D-asp) release (which mimics glutamate exocytosis). The concomitant [...] Read more.

The glutamatergic nerve endings of a rat prefrontal cortex (PFc) possess presynaptic 5-HT_2A heteroreceptors and mGlu2/3 autoreceptors, whose activation inhibits glutamate exocytosis, and is measured as 15 mM KCl-evoked [³H]D-aspartate ([³H]D-asp) release (which mimics glutamate exocytosis). The concomitant activation of the two receptors nulls their inhibitory activities, whereas blockade of the 5-HT_2A heteroreceptors with MDL11,939 (1 μM) strengthens the inhibitory effect elicited by the mGlu2/3 receptor agonist LY329268 (1 μM). 5-HT_2A receptor antagonists (MDL11,939; ketanserin; trazodone) amplify the impact of low (3 nM) LY379268. Clozapine (0.1–10 μM) mimics the 5-HT_2A agonist (±) DOI and inhibits the KCl-evoked [³H]D-asp overflow in a MDL11,939-dependent fashion, but does not modify the (±) DOI-induced effect. mGlu2 and 5-HT_2A proteins do not co-immunoprecipitate from synaptosomal lysates, nor does the incubation of PFc synaptosomes with MDL11,939 (1 μM) or clozapine (10 µM) modify the insertion of mGlu2 subunits in synaptosomal plasma membranes. In conclusion, 5-HT_2A and mGlu2/3 receptors colocalize, but do not physically associate, in PFc glutamatergic terminals, where they functionally interact in an antagonist-like fashion to control glutamate exocytosis. The mGlu2/3-5-HT_2A metamodulation could be relevant to therapy for central neuropsychiatric disorders, including schizophrenia, but also unveil cellular events accounting for their development, which also influence the responsiveness to drugs regimens. Full article

(This article belongs to the Special Issue The Role of Metabotropic Glutamate Receptors in Health and Disease)

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19 pages, 2333 KiB

Open AccessArticle

The Neuroprotective Effects of mGlu1 Receptor Antagonists Are Mediated by an Enhancement of GABAergic Synaptic Transmission via a Presynaptic CB1 Receptor Mechanism

by Elisa Landucci, Rolando Berlinguer-Palmini, Gilda Baccini, Francesca Boscia, Elisabetta Gerace, Guido Mannaioni and Domenico E. Pellegrini-Giampietro

Cells 2022, 11(19), 3015; https://doi.org/10.3390/cells11193015 - 27 Sep 2022

Cited by 2 | Viewed by 1955

Abstract

In this study, we investigated the cross-talk between mGlu1 and CB1 receptors in modulating GABA hippocampal output in whole-cell voltage clamp recordings in rat hippocampal acute slices, in organotypic hippocampal slices exposed to oxygen and glucose deprivation (OGD) and in gerbils subjected to [...] Read more.

In this study, we investigated the cross-talk between mGlu1 and CB1 receptors in modulating GABA hippocampal output in whole-cell voltage clamp recordings in rat hippocampal acute slices, in organotypic hippocampal slices exposed to oxygen and glucose deprivation (OGD) and in gerbils subjected to global ischemia. CB1 receptor expression was studied using immunohistochemistry and the CA1 contents of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) were measured by LC-MS/MS. Our results show that mGlu1 receptor antagonists enhance sIPSCs in CA1 pyramidal cells and the basal and ischemic hippocampal release of GABA in vivo in a manner that is mediated by CB1 receptor activation. In hippocampal slices exposed to OGD and in ischemic gerbils, mGlu1 receptor antagonists protected CA1 pyramidal cells against post-ischemic injury and this effect was reduced by CB1 receptor activation. OGD induced a transient increase in the hippocampal content of AEA and this effect is prevented by mGlu1 receptor antagonist. Finally, OGD induced a late disruption of CB1 receptors in the CA1 region and the effect was prevented when CA1 pyramidal cells were protected by mGlu1 antagonists. Altogether, these results suggest a cooperative interaction between mGlu1 receptors and the endocannabinoid system in the mechanisms that lead to post-ischemic neuronal death. Full article

(This article belongs to the Special Issue The Role of Metabotropic Glutamate Receptors in Health and Disease)

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13 pages, 2345 KiB

Open AccessCommunication

mGluR5 Is Substitutable for mGluR1 in Cerebellar Purkinje Cells for Motor Coordination, Developmental Synapse Elimination, and Motor Learning

by Maria Harbers, Harumi Nakao, Takaki Watanabe, Kyoko Matsuyama, Shoichi Tohyama, Kazuki Nakao, Yasushi Kishimoto, Masanobu Kano and Atsu Aiba

Cells 2022, 11(13), 2004; https://doi.org/10.3390/cells11132004 - 23 Jun 2022

Cited by 5 | Viewed by 3317

Abstract

Group I metabotropic glutamate receptors (mGluRs) include mGluR1 and mGluR5, which are coupled to the Gq family of heterotrimeric G-proteins and readily activated by their selective agonist 3,5-dihydroxyphenilglycine (DHPG). mGluR1 and mGluR5 exhibit nearly complementary distributions spatially or temporally in the central nervous [...] Read more.

Group I metabotropic glutamate receptors (mGluRs) include mGluR1 and mGluR5, which are coupled to the Gq family of heterotrimeric G-proteins and readily activated by their selective agonist 3,5-dihydroxyphenilglycine (DHPG). mGluR1 and mGluR5 exhibit nearly complementary distributions spatially or temporally in the central nervous system (CNS). In adult cerebellar Purkinje cells (PCs), mGluR1 is a dominant group I mGluR and mGluR5 is undetectable. mGluR1 expression increases substantially during the first three weeks of postnatal development and remains high throughout adulthood. On the other hand, mGluR5 expression is observed during the first two postnatal weeks and then decreases. However, functional differences between mGluR1 and mGluR5 in the CNS remains to be elucidated. To address this issue, we generated “mGluR5-rescue” mice in which mGluR5 is specifically expressed in PCs in global mGluR1-knockout (KO) mice. mGluR5-rescue mice exhibited apparently normal motor coordination, developmental elimination of redundant climbing fiber (CF)-PC synapses, and delay eyeblink conditioning, which were severely impaired in mGluR1-KO mice. We concluded that mGluR5 is functionally comparable with mGluR1 in cerebellar PCs. Full article

(This article belongs to the Special Issue The Role of Metabotropic Glutamate Receptors in Health and Disease)

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15 pages, 1374 KiB

Open AccessArticle

Blocking Metabotropic Glutamate Receptor Subtype 7 via the Venus Flytrap Domain Promotes a Chronic Stress-Resilient Phenotype in Mice

by Karolyne A. R. Estrela, Lisa Senninger, Josephine Arndt, Melanie Kabas, Ferdinand Schmid, Larissa Dillmann, Sophia Auer, Thomas Stepfer, Peter J. Flor and Nicole Uschold-Schmidt

Cells 2022, 11(11), 1817; https://doi.org/10.3390/cells11111817 - 2 Jun 2022

Cited by 3 | Viewed by 2904

Abstract

Chronic psychosocial stress participates prominently in the etiology of various psychiatric conditions and comorbid somatic pathologies; however, suitable pharmacotherapy of these disorders is still of high medical need. During the last few decades, research on mGlu receptors advanced remarkably and much attention was [...] Read more.

Chronic psychosocial stress participates prominently in the etiology of various psychiatric conditions and comorbid somatic pathologies; however, suitable pharmacotherapy of these disorders is still of high medical need. During the last few decades, research on mGlu receptors advanced remarkably and much attention was given to the mGlu7 subtype. Here, genetic mGlu7 ablation, short-term pharmacological mGlu7 blockade, as well as siRNA-mediated knockdown of mGlu7 were shown to result in an acute anti-stress, antidepressant- and anxiolytic-like phenotype in mice. Moreover, we recently revealed a prominent stress-protective effect of genetic mGlu7 ablation also with respect to chronic psychosocial stress. In addition, we are able to demonstrate in the present study that the chronic pharmacological blockade of mGlu7 interferes with various chronic stress-induced alterations. For this, we used the chronic subordinate colony housing (CSC), a mouse model of chronic male subordination, in combination with chronic treatment with the mGlu7-selective orthosteric-like antagonist XAP044 (7-hydroxy-3-(4-iodophenoxy)-4H-chromen-4-one). Interestingly, XAP044 dose-dependently ameliorates hypothalamic–pituitary–adrenal axis dysfunctions, thymus atrophy, as well as the CSC-induced increase in innate anxiety. Taken together, our findings provide further evidence for the role of mGlu7 in chronic psychosocial stress-induced alterations and suggests the pharmacological blockade of mGlu7 as a promising therapeutic approach for the treatment of chronic stress-related pathologies in men. Full article

(This article belongs to the Special Issue The Role of Metabotropic Glutamate Receptors in Health and Disease)

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24 pages, 4145 KiB

Open AccessArticle

Prevention of L-Dopa-Induced Dyskinesias by MPEP Blockade of Metabotropic Glutamate Receptor 5 Is Associated with Reduced Inflammation in the Brain of Parkinsonian Monkeys

by Marc Morissette, Mélanie Bourque, Marie-Ève Tremblay and Thérèse Di Paolo

Cells 2022, 11(4), 691; https://doi.org/10.3390/cells11040691 - 16 Feb 2022

Cited by 12 | Viewed by 3230

Abstract

Proinflammatory markers were found in brains of Parkinson’s disease (PD) patients. After years of L-Dopa symptomatic treatment, most PD patients develop dyskinesias. The relationship between inflammation and L-Dopa-induced dyskinesias (LID) is still unclear. We previously reported that MPEP (a metabotropic glutamate receptor 5 [...] Read more.

Proinflammatory markers were found in brains of Parkinson’s disease (PD) patients. After years of L-Dopa symptomatic treatment, most PD patients develop dyskinesias. The relationship between inflammation and L-Dopa-induced dyskinesias (LID) is still unclear. We previously reported that MPEP (a metabotropic glutamate receptor 5 antagonist) reduced the development of LID in de novo MPTP-lesioned monkeys. We thus investigated if MPEP reduced the brain inflammatory response in these MPTP-lesioned monkeys and the relationship to LID. The panmacrophage/microglia marker Iba1, the phagocytosis-related receptor CD68, and the astroglial protein GFAP were measured by Western blots. The L-Dopa-treated dyskinetic MPTP monkeys had increased Iba1 content in the putamen, substantia nigra, and globus pallidus, which was prevented by MPEP cotreatment; similar findings were observed for CD68 contents in the putamen and globus pallidus. There was a strong positive correlation between dyskinesia scores and microglial markers in these regions. GFAP contents were elevated in MPTP + L-Dopa-treated monkeys among these brain regions and prevented by MPEP in the putamen and subthalamic nucleus. In conclusion, these results showed increased inflammatory markers in the basal ganglia associated with LID and revealed that MPEP inhibition of glutamate activity reduced LID and levels of inflammatory markers. Full article

(This article belongs to the Special Issue The Role of Metabotropic Glutamate Receptors in Health and Disease)

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Review

Jump to: Research

16 pages, 1991 KiB

Open AccessReview

The Metabotropic Glutamate 5 Receptor in Sleep and Wakefulness: Focus on the Cortico-Thalamo-Cortical Oscillations

by Richard Teke Ngomba, Annika Lüttjohann, Aaron Dexter, Swagat Ray and Gilles van Luijtelaar

Cells 2023, 12(13), 1761; https://doi.org/10.3390/cells12131761 - 30 Jun 2023

Cited by 1 | Viewed by 1969

Abstract

Sleep is an essential innate but complex behaviour which is ubiquitous in the animal kingdom. Our knowledge of the distinct neural circuit mechanisms that regulate sleep and wake states in the brain are, however, still limited. It is therefore important to understand how [...] Read more.

Sleep is an essential innate but complex behaviour which is ubiquitous in the animal kingdom. Our knowledge of the distinct neural circuit mechanisms that regulate sleep and wake states in the brain are, however, still limited. It is therefore important to understand how these circuits operate during health and disease. This review will highlight the function of mGlu5 receptors within the thalamocortical circuitry in physiological and pathological sleep states. We will also evaluate the potential of targeting mGlu5 receptors as a therapeutic strategy for sleep disorders that often co-occur with epileptic seizures. Full article

(This article belongs to the Special Issue The Role of Metabotropic Glutamate Receptors in Health and Disease)

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20 pages, 1718 KiB

Open AccessReview

Psychedelic Targeting of Metabotropic Glutamate Receptor 2 and Its Implications for the Treatment of Alcoholism

by Kevin Domanegg, Wolfgang H. Sommer and Marcus W. Meinhardt

Cells 2023, 12(6), 963; https://doi.org/10.3390/cells12060963 - 22 Mar 2023

Cited by 12 | Viewed by 5007

Abstract

Alcohol abuse is a leading risk factor for the public health burden worldwide. Approved pharmacotherapies have demonstrated limited effectiveness over the last few decades in treating alcohol use disorders (AUD). New therapeutic approaches are therefore urgently needed. Historical and recent clinical trials using [...] Read more.

Alcohol abuse is a leading risk factor for the public health burden worldwide. Approved pharmacotherapies have demonstrated limited effectiveness over the last few decades in treating alcohol use disorders (AUD). New therapeutic approaches are therefore urgently needed. Historical and recent clinical trials using psychedelics in conjunction with psychotherapy demonstrated encouraging results in reducing heavy drinking in AUD patients, with psilocybin being the most promising candidate. While psychedelics are known to induce changes in gene expression and neuroplasticity, we still lack crucial information about how this specifically counteracts the alterations that occur in neuronal circuits throughout the course of addiction. This review synthesizes well-established knowledge from addiction research about pathophysiological mechanisms related to the metabotropic glutamate receptor 2 (mGlu2), with findings and theories on how mGlu2 connects to the major signaling pathways induced by psychedelics via serotonin 2A receptors (2AR). We provide literature evidence that mGlu2 and 2AR are able to regulate each other’s downstream signaling pathways, either through monovalent crosstalk or through the formation of a 2AR-mGlu2 heteromer, and highlight epigenetic mechanisms by which 2ARs can modulate mGlu2 expression. Lastly, we discuss how these pathways might be targeted therapeutically to restore mGlu2 function in AUD patients, thereby reducing the propensity to relapse. Full article

(This article belongs to the Special Issue The Role of Metabotropic Glutamate Receptors in Health and Disease)

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18 pages, 732 KiB

Open AccessReview

Role of mGlu5 in Persistent Forms of Hippocampal Synaptic Plasticity and the Encoding of Spatial Experience

by Hardy Hagena and Denise Manahan-Vaughan

Cells 2022, 11(21), 3352; https://doi.org/10.3390/cells11213352 - 24 Oct 2022

Cited by 8 | Viewed by 2080

Abstract

The metabotropic glutamate (mGlu) receptor family consists of group I receptors (mGlu1 and mGlu5) that are positively coupled to phospholipase-C and group II (mGlu2 and mGlu3) and III receptors (mGlu4-8) that are negatively coupled to adenylyl cyclase. Of these, mGlu5 has emerged as [...] Read more.

The metabotropic glutamate (mGlu) receptor family consists of group I receptors (mGlu1 and mGlu5) that are positively coupled to phospholipase-C and group II (mGlu2 and mGlu3) and III receptors (mGlu4-8) that are negatively coupled to adenylyl cyclase. Of these, mGlu5 has emerged as a key factor in the induction and maintenance of persistent (>24 h) forms of hippocampal synaptic plasticity. Studies in freely behaving rodents have revealed that mGlu5 plays a pivotal role in the stabilisation of hippocampal long-term potentiation (LTP) and long-term depression (LTD) that are tightly associated with the acquisition and retention of knowledge about spatial experience. In this review article we shall address the state of the art in terms of the role of mGlu5 in forms of hippocampal synaptic plasticity related to experience-dependent information storage and present evidence that normal mGlu5 function is central to these processes. Full article

(This article belongs to the Special Issue The Role of Metabotropic Glutamate Receptors in Health and Disease)

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21 pages, 2024 KiB

Open AccessReview

Implications of a Neuronal Receptor Family, Metabotropic Glutamate Receptors, in Cancer Development and Progression

by Kevinn Eddy, Mohamad Naser Eddin, Anna Fateeva, Stefano Vito Boccadamo Pompili, Raj Shah, Saurav Doshi and Suzie Chen

Cells 2022, 11(18), 2857; https://doi.org/10.3390/cells11182857 - 13 Sep 2022

Cited by 11 | Viewed by 4563

Abstract

Cancer is the second leading cause of death, and incidences are increasing globally. Simply defined, cancer is the uncontrolled proliferation of a cell, and depending on the tissue of origin, the cancer etiology, biology, progression, prognosis, and treatment will differ. Carcinogenesis and its [...] Read more.

Cancer is the second leading cause of death, and incidences are increasing globally. Simply defined, cancer is the uncontrolled proliferation of a cell, and depending on the tissue of origin, the cancer etiology, biology, progression, prognosis, and treatment will differ. Carcinogenesis and its progression are associated with genetic factors that can either be inherited and/or acquired and are classified as an oncogene or tumor suppressor. Many of these genetic factors converge on common signaling pathway(s), such as the MAPK and PI3K/AKT pathways. In this review, we will focus on the metabotropic glutamate receptor (mGluR) family, an upstream protein that transmits extracellular signals into the cell and has been shown to regulate many aspects of tumor development and progression. We explore the involvement of members of this receptor family in various cancers that include breast cancer, colorectal cancer, glioma, kidney cancer, melanoma, oral cancer, osteosarcoma, pancreatic cancer, prostate cancer, and T-cell cancers. Intriguingly, depending on the member, mGluRs can either be classified as oncogenes or tumor suppressors, although in general most act as an oncogene. The extensive work done to elucidate the role of mGluRs in various cancers suggests that it might be a viable strategy to therapeutically target glutamatergic signaling. Full article

(This article belongs to the Special Issue The Role of Metabotropic Glutamate Receptors in Health and Disease)

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40 pages, 1419 KiB

Open AccessReview

Recent Advances in the Modulation of Pain by the Metabotropic Glutamate Receptors

by Mariacristina Mazzitelli, Peyton Presto, Nico Antenucci, Shakira Meltan and Volker Neugebauer

Cells 2022, 11(16), 2608; https://doi.org/10.3390/cells11162608 - 21 Aug 2022

Cited by 9 | Viewed by 4051

Abstract

Metabotropic glutamate receptors (mGluR or mGlu) are G-protein coupled receptors activated by the binding of glutamate, the main classical neurotransmitter of the nervous system. Eight different mGluR subtypes (mGluR1-8) have been cloned and are classified in three groups based on their molecular, pharmacological [...] Read more.

Metabotropic glutamate receptors (mGluR or mGlu) are G-protein coupled receptors activated by the binding of glutamate, the main classical neurotransmitter of the nervous system. Eight different mGluR subtypes (mGluR1-8) have been cloned and are classified in three groups based on their molecular, pharmacological and signaling properties. mGluRs mediate several physiological functions such as neuronal excitability and synaptic plasticity, but they have also been implicated in numerous pathological conditions including pain. The availability of new and more selective allosteric modulators together with the canonical orthosteric ligands and transgenic technologies has led to significant advances in our knowledge about the role of the specific mGluR subtypes in the pathophysiological mechanisms of various diseases. Although development of successful compounds acting on mGluRs for clinical use has been scarce, the subtype-specific-pharmacological manipulation might be a compelling approach for the treatment of several disorders in humans, including pain; this review aims to summarize and update on preclinical evidence for the roles of different mGluRs in the pain system and discusses knowledge gaps regarding mGluR-related sex differences and neuroimmune signaling in pain. Full article

(This article belongs to the Special Issue The Role of Metabotropic Glutamate Receptors in Health and Disease)

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15 pages, 2048 KiB

Open AccessEditor’s ChoiceReview

Metabotropic Glutamate Receptors at Ribbon Synapses in the Retina and Cochlea

by Lisa Klotz-Weigand and Ralf Enz

Cells 2022, 11(7), 1097; https://doi.org/10.3390/cells11071097 - 24 Mar 2022

Cited by 3 | Viewed by 3727

Abstract

Our senses define our view of the world. They allow us to adapt to environmental stimuli and are essential for communication and social behaviour. For most humans, seeing and hearing are central senses for their daily life. Our eyes and ears respond to [...] Read more.

Our senses define our view of the world. They allow us to adapt to environmental stimuli and are essential for communication and social behaviour. For most humans, seeing and hearing are central senses for their daily life. Our eyes and ears respond to an extraordinary broad range of stimuli covering about 12 log units of light intensity or acoustic power, respectively. The cellular basis is represented by sensory cells (photoreceptors in the retina and inner hair cells in the cochlea) that convert sensory inputs into electrical signals. Photoreceptors and inner hair cells have developed a specific pre-synaptic structure, termed synaptic ribbon, that is decorated with numerous vesicles filled with the excitatory neurotransmitter glutamate. At these ribbon synapses, glutamatergic signal transduction is guided by distinct sets of metabotropic glutamate receptors (mGluRs). MGluRs belong to group II and III of the receptor classification can inhibit neuronal activity, thus protecting neurons from overstimulation and subsequent degeneration. Consequently, dysfunction of mGluRs is associated with vision and hearing disorders. In this review, we introduce the principle characteristics of ribbon synapses and describe group II and III mGluRs in these fascinating structures in the retina and cochlea. Full article

(This article belongs to the Special Issue The Role of Metabotropic Glutamate Receptors in Health and Disease)

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