Role Of Metabotropic Glutamate Receptors Research Articles

Effects of (S)-3,4-DCPG, an mGlu8 receptor agonist, on hippocampal long-term potentiation at perforant pathway-dentate gyrus synapses in prenatal valproic acid-induced rat model of autism

Autism spectrum disorder (ASD) is a pervasive neurodevelopmental condition characterized by social interaction deficits, communication impairments, repetitive behaviors, and sensory sensitivities. While the etiology of ASD is multifaceted, abnormalities in glutamatergic neurotransmission and synaptic plasticity have been implicated. This study investigated the role of metabotropic glutamate receptor 8 (mGlu8) in modulating long-term potentiation (LTP) in a rat model of ASD induced by prenatal valproic acid (VPA) exposure. To induce an animal model with autism-like characteristics, pregnant rats received an intraperitoneal injection of 500 mg/kg of sodium valproate (NaVPA) on embryonic day 12.5. High-frequency stimulation was applied to the perforant path-dentate gyrus (PP-DG) synapse to induce LTP, while the mGlu8 receptor agonist (S)-3,4-dicarboxyphenylglycine (DCPG) was administered into the DG. The results revealed that VPA-exposed rats exhibited reduced LTP compared to controls. DCPG had contrasting effects, inhibiting LTP in controls and enhancing it in VPA-exposed rats. Moreover, reduced social novelty preference index (SNPI) in VPA-exposed rats was reversed by intra-DG administration of S-3,4-DCPG. In conclusion, our study advances our understanding of the complex relationship between glutamatergic neurotransmission, synaptic plasticity, and VPA-induced autism model. The findings suggest that mGlu8 receptor dysfunction plays a role in the impaired synaptic plasticity seen in ASD.

Activation of mGluR1 negatively modulates glutamate-induced phase shifts of the circadian pacemaker in the mouse suprachiasmatic nucleus

In mammals, photic information delivered to the suprachiasmatic nucleus (SCN) via the retinohypothalamic tract (RHT) plays a crucial role in synchronizing the master circadian clock located in the SCN to the solar cycle. It is well known that glutamate released from the RHT terminals initiates the synchronizing process by activating ionotropic glutamate receptors (iGluRs) on retinorecipient SCN neurons. The potential role of metabotropic glutamate receptors (mGluRs) in modulating this signaling pathway has received less attention. In this study, using extracellular single-unit recordings in mouse SCN slices, we investigated the possible roles of the Gq/11 protein-coupled mGluRs, mGluR1 and mGluR5, in photic resetting. We found that mGluR1 activation in the early night produced phase advances in neural activity rhythms in the SCN, while activation in the late night produced phase delays. In contrast, mGluR5 activation had no significant effect on the phase of these rhythms. Interestingly, mGluR1 activation antagonized phase shifts induced by glutamate through a mechanism that was dependent upon CaV1.3 L-type voltage-gated Ca2+ channels (VGCCs). While both mGluR1-evoked phase delays and advances were inhibited by knockout (KO) of CaV1.3 L-type VGCCs, different signaling pathways appeared to be involved in mediating these effects, with mGluR1 working via protein kinase G in the early night and via protein kinase A signaling in the late night. We conclude that, in the mouse SCN, mGluR1s function to negatively modulate glutamate-evoked phase shifts.

Abstract 9101: RVLM Microinjection to Explain the Role of Metabotropic Glutamate Receptors in the Regulation of Baseline Blood Pressure and Heart Rate in SHRSP

Introduction: Glutamate (Glu) is activated by the stimulation of its receptors. The microinjection of Glu in rostral ventrolateral medulla (RVLM) elicited a rapid and large increase in blood pressure (BP) and heart rate (HR), which is inhibited with kynurenic acid (KYN), a selective inhibitor of ionotropic glutamate receptors (iGluR). Further, we showed that the response to Glu was much greater in stroke-prone spontaneously hypertensive rats (SHRSP) than that in Wistar Kyoto (WKY) rats, indicating that iGluR in RVLM played an important role to maintain high BP & HR in SHRSP. Whereas, the role of metabotropic glutamate receptors (mGluR) in RVLM were not fully elucidated in SHRSP yet. Hypotheses: Since the different mGluR types, e.g., group I (mGluR1, mGluR5), group II (mGluR2, mGluR3) & group III (mGluR4, mGluR6, mGluR7, mGluR8), are expressed in the various regions of rat’s brain, and several studies reported that mGluR5 is largely expressed in RVLM of rats; in this study we evaluated the pathophysiological role(s) of mGluR5, expecting that mGluR5 in RVLM keeps high baseline (i) BP and (ii) HR in SHRSP. Method: MTEP (10 nmole, a highly selective mGluR5 antagonist) and KYN (4 nmole) were microinjected unilaterally in RVLM in SHRSP (n=10) and WKY (n=10) to determine the effects on baseline BP & HR. In addition, the effects of two inhibitors on response to Glu (5 nmole) microinjection were observed. Results: MTEP reduced baseline BP & HR significantly in SHRSP when compared to those in WKY (ΔMAP: -30±3 vs. -3±2 mmHg, ΔHR: -35±3 vs. -4±2 bpm, respectively, p< 0.05), but failed to attenuate a response to Glu microinjection. In contrast, KYN had no significant effects on baseline BP & HR in the two strains, whereas it showed an inhibitory effect on the response to microinjected Glu, which was significantly greater in SHRSP than that in WKY. Conclusions: This study suggested that mGluR5 in RVLM played a major role in the maintenance of high baseline BP & HR in SHRSP.

Metabotropic glutamate receptors and nitric oxide in dopaminergic neurotoxicity.

Dopaminergic neurotoxicity is characterized by damage and death of dopaminergic neurons. Parkinson's disease (PD) is a neurodegenerative disorder that primarily involves the loss of dopaminergic neurons in the substantia nigra. Therefore, the study of the mechanisms, as well as the search for new targets for the prevention and treatment of neurodegenerative diseases, is an important focus of modern neuroscience. PD is primarily caused by dysfunction of dopaminergic neurons; however, other neurotransmitter systems are also involved. Research reports have indicated that the glutamatergic system is involved in different pathological conditions, including dopaminergic neurotoxicity. Over the last two decades, the important functional interplay between dopaminergic and glutamatergic systems has stimulated interest in the possible role of metabotropic glutamate receptors (mGluRs) in the development of extrapyramidal disorders. However, the specific mechanisms driving these processes are presently unclear. The participation of the universal neuronal messenger nitric oxide (NO) in the mechanisms of dopaminergic neurotoxicity has attracted increased attention. The current paper aims to review the involvement of mGluRs and the contribution of NO to dopaminergic neurotoxicity. More precisely, we focused on studies conducted on the rotenone-induced PD model. This review is also an outline of our own results obtained using the method of electron paramagnetic resonance, which allows quantitation of NO radicals in brain structures.

Neonatal maternal separation affects metabotropic glutamate receptor 5 expression and anxiety-related behavior of adult rats.

Exposure to early life stress leads to long-term neurochemical and behavioral alterations. Stress-induced psychiatric disorders, such as depression, have recently been linked to dysregulation of glutamate signaling, mainly via its postsynaptic receptors. The role of metabotropic glutamate receptor 5 (mGluR5) in stress-induced psychopathology has been the target of several studies in humans. In rodents, blockade of mGluR5 produces antidepressant-like actions, whereas mice lacking mGluR5 exhibit altered anxiety-like behaviors and learning. In this study, we used well-known rodent models of early life stress based on mother-infant separation during the first 3 weeks of life in order to examine the effects of neonatal maternal separation on mGluR5 expression and on anxiety-related behavior in adulthood. We observed that brief (15 min) neonatal maternal separation, but not prolonged (3h), induced increases in mGluR5 mRNA and protein expression levels in medial prefrontal cortex and mGluR5 protein levels in dorsal, but not ventral, hippocampus of adult rat brain. Behavioral testing using the open-field and the elevated-plus maze tasks showed that brief maternal separations resulted in increased exploratory and decreased anxiety-related behavior, whereas prolonged maternal separations resulted in increased anxiety-related behavior in adulthood. The data indicate that the long-lasting effects of neonatal mother-offspring separation on anxiety-like behavior and mGluR5 expression depend on the duration of maternal separation and suggest that the increased mGluR5 receptors in medial prefrontal cortex and hippocampus of adult rats exposed to brief neonatal maternal separations may underlie their heightened ability to cope with stress.

The G Protein-Coupled Glutamate Receptors as Novel Molecular Targets in Schizophrenia Treatment—A Narrative Review

Schizophrenia is a severe neuropsychiatric disease with an unknown etiology. The research into the neurobiology of this disease led to several models aimed at explaining the link between perturbations in brain function and the manifestation of psychotic symptoms. The glutamatergic hypothesis postulates that disrupted glutamate neurotransmission may mediate cognitive and psychosocial impairments by affecting the connections between the cortex and the thalamus. In this regard, the greatest attention has been given to ionotropic NMDA receptor hypofunction. However, converging data indicates metabotropic glutamate receptors as crucial for cognitive and psychomotor function. The distribution of these receptors in the brain regions related to schizophrenia and their regulatory role in glutamate release make them promising molecular targets for novel antipsychotics. This article reviews the progress in the research on the role of metabotropic glutamate receptors in schizophrenia etiopathology.

MGlu3 receptor regulates microglial cell reactivity in neonatal rats

BackgroundPerinatal inflammation is a key factor of brain vulnerability in neonates born preterm or with intra-uterine growth restriction (IUGR), two leading conditions associated with brain injury and responsible for neurocognitive and behavioral disorders. Systemic inflammation is recognized to activate microglia, known to be the critical modulators of brain vulnerability. Although some evidence supports a role for metabotropic glutamate receptor 3 (mGlu3 receptor) in modulation of neuroinflammation, its functions are still unknown in the developing microglia.MethodsWe used a double-hit rat model of perinatal brain injury induced by a gestational low-protein diet combined with interleukin-1β injections (LPD/IL-1β), mimicking both IUGR and prematurity-related inflammation. The effect of LPD/IL-1β on mGlu3 receptor expression and the effect of mGlu3 receptor modulation on microglial reactivity were investigated using a combination of pharmacological, histological, and molecular and genetic approaches.ResultsExposure to LPD/IL-1β significantly downregulated Grm3 gene expression in the developing microglia. Both transcriptomic analyses and pharmacological modulation of mGlu3 receptor demonstrated its central role in the control of inflammation in resting and activated microglia. Microglia reactivity to inflammatory challenge induced by LPD/IL-1β exposure was reduced by an mGlu3 receptor agonist. Conversely, both specific pharmacological blockade, siRNA knock-down, and genetic knock-out of mGlu3 receptors mimicked the pro-inflammatory phenotype observed in microglial cells exposed to LPD/IL-1β.ConclusionsOverall, these data show that Grm3 plays a central role in the regulation of microglial reactivity in the immature brain. Selective pharmacological activation of mGlu3 receptors may prevent inflammatory-induced perinatal brain injury.

Mutations in Metabotropic Glutamate Receptor 1 Contribute to Natural Short Sleep Trait

Sufficient and efficient sleep is crucial for our health. Natural short sleepers can sleep significantly shorter than the average population without a desire for more sleep and without any obvious negative health consequences. In searching for genetic variants underlying the short sleep trait, we found two different mutations in the same gene (metabotropic glutamate receptor 1) from two independent natural short sleep families. Invitro, both of the mutations exhibited loss of function in receptor-mediated signaling. Invivo, the mice carrying the individual mutations both demonstrated short sleep behavior. In brain slices, both of the mutations changed the electrical properties and increased excitatory synaptic transmission. These results highlight the important role of metabotropic glutamate receptor 1 in modulating sleep duration.

The metabotropic glutamate receptor 2/3 antagonist LY341495 improves working memory in adult mice following juvenile social isolation

Juvenile social isolation (SI) and neglect have a negative impact on neurodevelopment persistently, which is associated with cognitive dysfunction in neurodevelopmental disorders. Given the critical role of metabotropic glutamate receptors (mGluRs) in synaptic homeostasis of the prefrontal cortex (PFC), pharmacological intervention on mGluRs has been attempted in order to improve cognitive dysfunction in animal models of neurodevelopmental disorder, as well as in clinical trials. Here we examined the effects of the mGluR2/3 antagonist LY341495 on prefrontal synaptic transmission, spatial working memory, and recognition memory in adult C57BL/6J mice that experienced juvenile SI. We found that SI-reared mice exhibited working memory impairment and decreased excitatory presynaptic release probability of pyramidal neurons in the medial PFC compared with group-reared mice. The positive effect of LY341495 on excitatory synaptic transmission in SI-reared mice was more prominent than the effect in group-reared mice. A single treatment with mGluR2/3 antagonist LY341495 significantly improved the performance of SI-reared mice in the Y-maze test but not in the novel object recognition (NOR) test, while repeated treatments were effective in both tasks. These findings suggest that enhancing glutamatergic transmission via inhibition of mGluR2/3 signaling might represent a promising strategy for improving cognitive function in neurodevelopmental disorders.

The Role of Metabotropic Glutamate Receptors in Cerebellar Dysfunction in Multiple Sclerosis (1015)

The Role of Metabotropic Glutamate Receptors in Cerebellar Dysfunction in Multiple Sclerosis (1015)

Antiparkinsonian Effects of a Metabotropic Glutamate Receptor 4 Agonist in MPTP-Treated Marmosets

Increased firing across glutamatergic synapses may contribute to both the motor dysfunction and L-DOPA-induced dyskinesia seen in Parkinson's disease. Given their ability to reduce glutamate release, activation of group III metabotropic glutamate receptors such as metabotropic glutamate receptor 4 may prove effective against both motor dysfunction and dyskinesia in Parkinson's disease. We hypothesised that activation of metabotropic glutamate receptor 4 by an orthosteric agonist ((2S)-2-amino-4-(hydroxy(hydroxy(4-hydroxy-3-methoxy-5-nitrophenyl)methyl)phosphoryl)butanoic acid, LSP1-2111) would produce antiparkinsonian activity and reduce expression of dyskinesia in a 1-methyl-4-phenyl,1,2,3,6-tetrahydropyridine (MPTP)-treated marmoset model of Parkinson's disease. Common marmosets were previously treated with MPTP and pre-primed with L-DOPA for up to 28 days to express dyskinesia. LSP1-2111 (1, 3, or 6 mg/kg s.c.) or vehicle (0.9% saline s.c.) were administered immediately prior to L-DOPA (8 mg/kg + benserazide (10 mg/kg) p.o.) or vehicle (10% sucrose p.o.). Locomotor activity was measured in automated test cages and animals were scored for dyskinesia and disability. As expected, L-DOPA reversed motor disability and induced moderate dyskinesia. By contrast, LSP1-2111 alone significantly reduced the motor disability without any accompanying expression of dyskinesia. When administered in combination with L-DOPA, LSP1-2111 did not significantly reduce the severity of L-DOPA-induced dyskinesia. Systemic administration of LSP1-2111 reduces motor disability without causing dyskinesia in MPTP-treated marmosets, supporting a role for metabotropic glutamate receptor 4 orthosteric agonists as promising monotherapy for PD. Conversely, this study found no evidence to support their use as antidyskinetic agents within the dose range tested.

Critical role of metabotropic glutamate receptor 4 in bone marrow-derived dendritic cells in the Th17 cell differentiation and the melanogenesis of B16 cells.

Vitiligo is an acquired pigmentary disorder resulting from selective destruction of melanocytes. Emerging studies have suggested that T helper cell 17 (Th17) is potentially implicated in vitiligo development and progression. It was recently discovered that metabotropic glutamate receptor 4 (mGluR4) can modulate Th17-mediated adaptive immunity. However, the influence of mGluR4 on melanogenesis of melanocytes has yet to be elucidated. In the present study, we primarily cultured mouse bone marrow-derived dendritic cells (BMDC) and then knocked down and over-expressed mGluR4 using transfection. Transduced BMDC were co-cultured with CD4+ T cells and the expression of Th17-related cytokines were measured. The morphology and melanogenesis of B16 cells were observed after being treated with co-culture medium of CD4+ T cells and transduced BMDC. We found that mGluR4 knockdown did not affect the co-stimulatory CD80 and CD86 upregulation after lipopolysaccharide stimulation but did increase the expression of Th17-related cytokines, and further down-regulated the expression of microphthalmia-associated transcription factor (MITF) and the downstream genes, decreased melanin production, and destroyed the morphology of B16 cells. Conversely, over-expression of mGluR4 reduced the expression of CD80 and CD86, suppressed the production of Th17-related cytokines, increased the expression of MITF, and did not destroy the morphology of B16 cells. Our study confirmed that mGluR4 modulated the Th17 cell polarization and resulted in the alteration of melanogenesis and morphology of B16 cells. Collectively, these findings suggest mGluR4 might be a potent target involved in the immune pathogenesis of vitiligo.

Abstract 1839: Concurrent inhibition of glutaminase (GLS) and metabotropic receptor 1 (GRM1) reduced glutamate bioavailability and led to a decrease in GRM1-expressing melanoma cell proliferation in vitro and tumor progression in vivo

Abstract Aberrant glutamatergic signaling has been implicated in multiple metabolic processes and several types of cancer. Our laboratory has previously illustrated the role of metabotropic glutamate receptor 1 (GRM1), a G-protein coupled receptor, in neoplastic transformation of melanocytes in vitro and spontaneous development of metastatic melanoma in vivo. Here, we demonstrate significant overexpression of glutaminase (GLS) in GRM1 expressing melanoma cells, resulting in excess production of GRM1’s natural ligand, glutamate, and the establishment of autocrine loops. GLS catalyzes the first step in glutamine metabolism–the conversion of glutamine to glutamate before entering the TCA cycle. Comparison of glutamate levels in circulating blood plasma between melanoma prone GRM1-transgenic and wild type mice showed elevated glutamate levels in melanoma prone GRM1-transgenic mice, suggesting that aberrant GRM1 expression also promotes an increase in circulating glutamate, to ensure constitutive activation of the GRM1 receptor and its downstream signaling effecters in vivo. We also discovered that manipulation of GRM1 expression by genetic means led to robust parallel changes in metabolite expression levels and intracellular glutamate concentrations by mass spectrometry analysis, as well as the endogenous levels of GLS in melanoma cells, suggesting a strong association between GRM1 and GLS. Inclusion of CB-839, a potent, selective, and orally bioavailable inhibitor of GLS, resulted in significant inhibition of GRM1+ melanoma cell proliferation compared to GRM1- ones. The sensitivity of GRM1+ melanoma cells to modulation of GLS points to the dependency of these cells to glutamate amounts via GLS activity. We also demonstrated that treatment with Riluzole, an inhibitor of glutamatergic signaling by decreasing the available ligand, glutamate, led to significantly reduced melanoma cell proliferation in vitro and tumor progression in vivo. We found that simultaneous targeting of glutamate production (CB-839) and release (Riluzole) in GRM1+ melanoma cells led to additive suppression of cell proliferation in vitro. Most importantly, disruption of GRM1 signaling through combined actions of CB-839 and Riluzole significantly suppressed tumor growth in two independent xenograft mouse models of melanoma, with no obvious symptoms of toxicity detected in these mice. Taken together, these results describe a novel pathway for GRM1-mediated tumorigenesis through rewiring of cellular metabolic networks. We are continuing to investigate the mechanisms and regulation of GLS in our experimental system, with the goal of developing a rational strategy for the treatment of GRM1-expressing cancers. Citation Format: Raj Shah, Simar Singh, Kevinn Eddy, Fabian Filipp, Suzie Chen. Concurrent inhibition of glutaminase (GLS) and metabotropic receptor 1 (GRM1) reduced glutamate bioavailability and led to a decrease in GRM1-expressing melanoma cell proliferation in vitro and tumor progression in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1839.

Role of mGluR5 in laterocapcular division of central nucleus of amygdala in fentanyl-induced hyperalgesia in rats

To investigate the role of metabotropic glutamate receptor 5 (mGluR5) in laterocapcular division of the central nucleus of amygdala (CeLC) in fentanyl-induced hyperalgesia in rats. Methods: A total of 12 Sprague-Dawley male rats (60-100 g) were randomly divided into a normal group 1 (n=6) and an opioid-induced hyperalgesia (OIH) group 1 (n=6). The OIH group 1 was injected with fentanyl through the lower neck skin to build OIH model, and the normal group 1 was given the same volume of saline. After 6.5 h, paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) were tested to verify the success of the induction of OIH. Then rats were sacrificed and the right CeLC tissue were taken for detection of the mGluR5 by Western blotting. Forty SD male rats were randomly divided into 4 groups (n=10 each): an OIH+DMSO, an OIH+MTEP (3.0 μg), an OIH+MTEP (7.5 μg) and an OIH+MTEP (15.0 μg) group. MTEP was a selective antagonist of mGluR5. Catheterization in the right CeLC was first performed. After one-week recovery, OIH was induced. Then 0.5 μL DMSO, MTEP 3.0 μg, MTEP 7.5 μg and MTEP 15.0 μg were administrated through the CeLC catheter accordingly. PWMT and PWTL were tested at pre-OIH, 6 h after OIH and post-drug. Then the expression levels of mGluR5 of CeLC tissue were analyzed by Western blotting. Another 8 SD male rats were randomly divided into a normal group 2 and an OIH group 2 (n=4 each). The rats were induced OIH by injecting of fentanyl while rats in the normal group 2 were injected with same volume of saline. The miniature excitatory postsynaptic currents (mEPSCs) of the 2 groups' neurons in the right CeLC region were recorded by whole cell voltage-clamp before and after the administration of MTEP in brain slice. Results: Compared with the normal group 1, the PWTL and PWMT were significantly decreased and the expression of mGluR5 was apparently increased in the OIH group 1 (P<0.05). The PWMT and PWTL were significantly decreased in each group and indicated success of OIH model (P<0.05). The expression of mGluR5 in the CeLC was increased. MTEP reversed these changes in a dose-dependent way (P<0.05). Compared with the normal group 2, the amplitude and frequency of mEPSCs in the OIH group 2 were significantly increased (P<0.05) and they were reversed by MTEP (P<0.05). Conclusion: mGluR5 in the CeLC may be involved in the maintenance of OIH. Inhibition of the activity of mGluR5 in the CeLC may alleviate the symptoms of fentanyl-induced hyperalgesia.

Concurrent Targeting of Glutaminolysis and Metabotropic Glutamate Receptor 1 (GRM1) Reduces Glutamate Bioavailability in GRM1+ Melanoma.

Aberrant glutamatergic signaling has been implicated in altered metabolic activity in many cancer types, including malignant melanoma. Previously, we have illustrated the role of metabotropic glutamate receptor 1 (GRM1) in neoplastic transformation of melanocytes in vitro and spontaneous metastatic melanoma in vivo. In this study, we showed that autocrine stimulation constitutively activates the GRM1 receptor and its downstream mitogenic signaling. GRM1-activated (GRM1+) melanomas exhibited significantly increased expression of glutaminase (GLS), which catalyzes the first step in the conversion of glutamine to glutamate. In cultured GRM1+ melanoma cell lines, CB-839, a potent, selective, and orally bioavailable inhibitor of GLS, suppressed cell proliferation, while riluzole, an inhibitor of glutamate release, promoted apoptotic cell death in vitro and in vivo. Combined treatment with CB-839 and riluzole treatment proved to be superior to single-agent treatment, restricting glutamate bioavailability and leading to effective suppression of tumor cell proliferation in vitro and tumor progression in vivo. Hyperactivation of GRM1 in malignant melanoma is an oncogenic driver, which acts independently of canonical melanoma proto-oncogenes, BRAF or NRAS. Overall, these results indicate that expression of GRM1 promotes a metabolic phenotype that supports increased glutamate production and autocrine glutamatergic signaling, which can be pharmacologically targeted by decreasing glutamate bioavailability and the GLS-dependent glutamine to glutamate conversion. SIGNIFICANCE: These findings demonstrate that targeting glutaminolytic glutamate bioavailability is an effective therapeutic strategy for GRM1-activated tumors.

The Role of Metabotropic Glutamate Receptors in Social Behavior in Rodents.

The appropriate display of social behavior is critical for the well-being and survival of an individual. In many psychiatric disorders, including social anxiety disorder, autism spectrum disorders, depression and schizophrenia social behavior is severely impaired. Selective targeting of metabotropic glutamate receptors (mGluRs) has emerged as a novel treatment strategy for these disorders. In this review, we describe some of the behavioral paradigms used to assess different types of social behavior, such as social interaction, social memory, aggressive behavior and sexual behavior. We then focus on the effects of pharmacological modulation of mGluR1-8 on these types of social behavior. Indeed, accumulating evidence indicates beneficial effects of selective ligands of specific mGluRs in ameliorating innate or pharmacologically-induced deficits in social interaction and social memory as well as in reducing aggression in rodents. We emphasize the importance of future studies investigating the role of selective mGluR ligands on different types of social behavior to provide a better understanding of the neural mechanisms involved which, in turn, might promote the development of selective mGluR-targeted tools for the improved treatment of psychiatric disorders associated with social deficits.

Increased Alcohol-Drinking Induced by Manipulations of mGlu5 Phosphorylation within the Bed Nucleus of the Stria Terminalis.

The bed nucleus of the stria terminalis (BNST) is part of the limbic-hypothalamic system important for behavioral responses to stress, and glutamate transmission within this region has been implicated in the neurobiology of alcoholism. Herein, we used a combination of immunoblotting, neuropharmacological and transgenic procedures to investigate the role for metabotropic glutamate receptor 5 (mGlu5) signaling within the BNST in excessive drinking. We discovered that mGlu5 signaling in the BNST is linked to excessive alcohol consumption in a manner distinct from behavioral or neuropharmacological endophenotypes that have been previously implicated as triggers for heavy drinking. Our studies demonstrate that, in male mice, a history of chronic binge alcohol-drinking elevates BNST levels of the mGlu5-scaffolding protein Homer2 and activated extracellular signal-regulated kinase (ERK) in an adaptive response to limit alcohol consumption. Male and female transgenic mice expressing a point mutation of mGlu5 that cannot be phosphorylated by ERK exhibit excessive alcohol-drinking, despite greater behavioral signs of alcohol intoxication and reduced anxiety, and are insensitive to local manipulations of signaling in the BNST. These transgenic mice also show selective insensitivity to alcohol-aversion and increased novelty-seeking, which may be relevant to excessive drinking. Further, the insensitivity to alcohol-aversion exhibited by male mice can be mimicked by the local inhibition of ERK signaling within the BNST. Our findings elucidate a novel mGluR5-linked signaling state within BNST that plays a central and unanticipated role in excessive alcohol consumption.SIGNIFICANCE STATEMENT The bed nucleus of the stria terminalis (BNST) is part of the limbic-hypothalamic system important for behavioral responses to stress and alcohol, and glutamate transmission within BNST is implicated in the neurobiology of alcoholism. The present study provides evidence that a history of excessive alcohol drinking increases signaling through the metabotropic glutamate receptor 5 (mGlu5) receptor within the BNST in an adaptive response to limit alcohol consumption. In particular, disruption of mGlu5 phosphorylation by extracellular signal-regulated kinase within this brain region induces excessive alcohol-drinking, which reflects a selective insensitivity to the aversive properties of alcohol intoxication. These data indicate that a specific signaling state of mGlu5 within BNST plays a central and unanticipated role in excessive alcohol consumption.

Role of Metabotropic Glutamate Receptors in Neurological Disorders.

Glutamate is a fundamental excitatory neurotransmitter in the mammalian central nervous system (CNS), playing key roles in memory, neuronal development, and synaptic plasticity. Moreover, excessive glutamate release has been implicated in neuronal cell death. There are both ionotropic and metabotropic glutamate receptors (mGluRs), the latter of which can be divided into eight subtypes and three subgroups based on homology sequence and their effects on cell signaling. Indeed, mGluRs exert fine control over glutamate activity by stimulating several cell-signaling pathways via the activation of G protein-coupled (GPC) or G protein-independent cell signaling. The involvement of specific mGluRs in different forms of synaptic plasticity suggests that modulation of mGluRs may aid in the treatment of cognitive impairments related to several neurodevelopmental/psychiatric disorders and neurodegenerative diseases, which are associated with a high economic and social burden. Preclinical and clinical data have shown that, in the CNS, mGluRs are able to modulate presynaptic neurotransmission by fine-tuning neuronal firing and neurotransmitter release in a dynamic, activity-dependent manner. Current studies on drugs that target mGluRs have identified promising, innovative pharmacological tools for the treatment of neurodegenerative and neuropsychiatric conditions, including chronic pain.

GRM7 polymorphisms and risk of schizophrenia in Iranian population.

The role of metabotropic glutamate receptors in the pathogenesis of schizophrenia or response to antipsychotic treatment has been proposed previously. The aim of the current study was to investigate the associations between two intronic variants within GRM7 gene (rs6782011 and rs779867) and schizophrenia in Iranian population. These two single nucleotide polymorphisms (SNPs) were genotyped in 273 schizophrenic patients and 300 age and sex-matched normal controls. The frequency of A allele of the rs779867 was significantly lower in the schizophrenic patients compared with healthy subjects (OR (95% CI) = 0.71 (0.56-0.89), adjusted P value = 0.008). This SNP was associated with schizophrenia in co-dominant and dominant models (adjusted P values of 0.03 and 0.02 respectively). However, there was no difference in allele and genotype frequencies of the rs6782011 SNP between cases and controls. Consequently, the results of current study further highlight the participation of GRM7 in the pathogenesis of schizophrenia.

The Role of Metabotropic Glutamate Receptor 1 Dependent Signaling in Glioma Viability

Glioma refers to malignant central nervous system tumors that have histologic characteristics in common with glial cells. The most prevalent type, glioblastoma multiforme, is associated with a poor prognosis and few treatment options. On the basis of reports of aberrant expression of mGluR1 mRNA in glioma, evidence that melanoma growth is directly influenced by glutamate metabotropic receptor 1 (mGluR1), and characterization of β-arrestin-dependent prosurvival signaling by this receptor, this study investigated the hypothesis that glioma cell lines aberrantly express mGluR1 and depend on mGluR1-mediated signaling to maintain viability and proliferation. Three glioma cell lines (Hs683, A172, and U87) were tested to confirm mGluR1 mRNA expression and the dependence of glioma cell viability on glutamate. Pharmacologic and genetic evidence is presented that suggests mGluR1 signaling specifically supports glioma proliferation and viability. For example, selective noncompetitive antagonists of mGluR1, CPCCOEt and JNJ16259685, decreased the viability of these cells in a dose-dependent manner, and glutamate metabotropic receptor 1 gene silencing significantly reduced glioma cell proliferation. Also, results of an anchorage-independent growth assay suggested that noncompetitive antagonism of mGluR1 may decrease the tumorigenic potential of Hs683 glioma cells. Finally, data are provided that support the hypothesis that a β-arrestin-dependent signaling cascade may be involved in glutamate-stimulated viability in glioma cells and that ligand bias may exist at mGluR1 expressed in these cells. Taken together, the results strongly suggest that mGluR1 may act as a proto-oncogene in glioma and be a viable drug target in glioma treatment.