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Background and Purpose: Metabotropic glutamate receptor 1 (mGlu1) is a promising therapeutic target for neurodegenerative CNS disorders including spinocerebellar ataxias (SCAs). Clinical reports have identified naturally‐occurring mGlu1 mutations in rare SCA subtypes and linked symptoms to mGlu1 mutations. However, how mutations alter mGlu1 function remains unknown, as does amenability of receptor function to pharmacological rescue. Here, we explored SCA‐associated mutation effects on mGlu1 cell surface expression, canonical signal transduction and allosteric ligand pharmacology. Experimental Approach: Orthosteric agonists, positive allosteric modulators (PAMs) and negative allosteric modulators (NAMs) were assessed at two functional endpoints (iCa2+ mobilisation and inositol 1‐phosphate [IP1] accumulation) in FlpIn Trex HEK293A cell lines expressing five mutant mGlu1 subtypes. Key pharmacological parameters including ligand potency, affinity and cooperativity were derived using operational models of agonism and allostery. Key Results: mGlu1 mutants exhibited differential impacts on mGlu1 expression, with a C‐terminus truncation significantly reducing surface expression. Mutations differentially influenced orthosteric ligand affinity, efficacy and functional cooperativity between allosteric and orthosteric ligands. Loss‐of‐function mutations L454F and N885del reduced orthosteric affinity and efficacy, respectively. A gain‐of‐function Y792C mutant mGlu1 displayed enhanced constitutive activity in IP1 assays, which manifested as reduced orthosteric agonist activity. The mGlu1 PAMs restored glutamate potency in iCa2+ mobilisation for loss‐of‐function mutations and mGlu1 NAMs displayed enhanced inverse agonist activity at Y792C relative to wild‐type mGlu1. Conclusion and Implications: Collectively, these data highlight distinct mechanisms by which mGlu1 mutations affect receptor function and show allosteric modulators may present a therapeutic strategy to restore aberrant mGlu1 function in rare SCA subtypes. [ABSTRACT FROM AUTHOR]

Group I metabotropic glutamate receptors (Gp1-mGluRs) exert a host of effects on cellular functions, including enhancement of protein synthesis and the associated facilitation of long-term potentiation (LTP) and induction of long-term depression (LTD). However, the complete cascades of events mediating these events are not fully understood. Gp1-mGluRs trigger α-secretase cleavage of amyloid precursor protein, producing soluble amyloid precursor protein-α (sAPPα), a known regulator of LTP. However, the α-cleavage of APP has not previously been linked to Gp1-mGluR's actions. Using rat hippocampal slices, we found that the α-secretase inhibitor tumour necrosis factor-alpha protease inhibitor-1, which inhibits both disintegrin and metalloprotease 10 (ADAM10) and 17 (ADAM17) activity, blocked or reduced the ability of the Gp1-mGluR agonist (R,S)-3,5-dihydroxyphenylglycine (DHPG) to stimulate protein synthesis, metaplastically prime future LTP and elicit sub-maximal LTD. In contrast, the specific ADAM10 antagonist GI254023X did not affect the regulation of plasticity, suggesting that ADAM17 but not ADAM10 is involved in mediating these effects of DHPG. However, neither drug affected LTD that was strongly induced by either high-concentration DHPG or paired-pulse synaptic stimulation. Our data suggest that moderate Gp1-mGluR activation triggers α-secretase sheddase activity targeting APP or other membrane-bound proteins as part of a more complex signalling cascade than previously envisioned. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'. [ABSTRACT FROM AUTHOR]

[Display omitted] • Repeated social defeat stress model is ideal to investigate preventive and therapeutic measures for depressive-like behavior. • Partnership intervention prevents depressive-like behavior induced by repeated social defeat stress. • Single dose of 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide treatment alleviates social avoidance behavior. Persistent stress increases the probability for developing depression significantly thereafter. Repeated social defeat stress is a widely used model to investigate depressive-like behavior in preclinical models. Hence, the repeated social defeat stress model provided an ideal animal model, through which the hypotheses of prevention and treatment can be investigated. We have successfully induced depressive-like behavior for male C57BL/6J mice with this model. Here, we reported that certain level of during-stress social interactions with single female or multiple male peer(s) exerted a positive role in preventing the development of depressive-like behavior induced by repeated social defeat stress. Our data suggested that the stress-susceptible mice may benefit from positive social interaction, which reduces the chance for depressive-like behavior development. Since numerous studies indicate that the metabotropic glutamate receptor 5 (mGluR5) plays an important role in various cognitive functions, we further investigate the treatment effect of 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB) on the depressive-like behavior induced by repeated social defeat stress. Most importantly, robust anti-depressant effects have been achieved through modulating the mGluR5 function. We found that single oral dose administration of CDPPB (20 mg/kg), to some extent, alleviated the social avoidance behaviors for the stress-susceptible mice. Our data implies that the CDPPB, a positive allosteric modulator of mGluR5, is a promising anti-depressant candidate with limited side effect. [ABSTRACT FROM AUTHOR]

• T cells in the chronically infected brain express metabotropic glutamate receptors. • Using flow cytometry and scRNAseq analysis, mGluR expressing T cells are a defined subset of CD8+ T cells with a memory phenotype. • Production of IFN-g depends on mGluR stimulation. Within the brain, a pro-inflammatory response is essential to prevent clinical disease due to Toxoplasma gondii reactivation. Infection in the immunocompromised leads to lethal Toxoplasmic encephalitis while in the immunocompetent, there is persistent low-grade inflammation which is devoid of clinical symptoms. This signifies that there is a well-balanced and regulated inflammatory response to T. gondii in the brain. T cells are the dominant immune cells that prevent clinical disease, and this is mediated through the secretion of effector molecules such as perforins and IFN-γ. The presence of cognate antigen, the expression of survival cytokines, and the alteration of the epigenetic landscape drive the development of memory T cells. However, specific extrinsic signals that promote the formation and maintenance of memory T cells within tissue are poorly understood. During chronic infection, there is an increase in extracellular glutamate that, due to its function as an excitatory neurotransmitter, is normally tightly controlled in the CNS. Here we demonstrate that CD8+ T cells from the T. gondii -infected brain parenchyma are enriched for metabotropic glutamate receptors (mGluR's). Characterization studies determined that mGluR+ expression by CD8+ T cells defines a distinct memory population at the transcriptional and protein level. Finally, using receptor antagonists and agonists we demonstrate mGluR signaling is required for optimal CD8+ T cell production of the effector cytokine IFNγ. This work suggests that glutamate is an important environmental signal of inflammation that promotes T cell function. Understanding glutamate's influence on T cells in the brain can provide insights into the mechanisms that govern protective immunity against CNS-infiltrating pathogens and neuroinflammation. [ABSTRACT FROM AUTHOR]

Abstract Background Neurodevelopmental disorders (NDDs), such as attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), are examples of complex and partially overlapping phenotypes that often lack definitive corroborating genetic information. ADHD and ASD have complex genetic associations implicated by rare recurrent copy number variations (CNVs). Both of these NDDs have been shown to share similar biological etiologies as well as genetic pleiotropy. Methods Platforms aimed at investigating genetic-based associations, such as high-density microarray technologies, have been groundbreaking techniques in the field of complex diseases, aimed at elucidating the underlying disease biology. Previous studies have uncovered CNVs associated with genes within shared candidate genomic networks, including glutamate receptor genes, across multiple different NDDs. To examine shared biological pathways across two of the most common NDDs, we investigated CNVs across 15,689 individuals with ADHD (n = 7920), ASD (n = 4318), or both (n = 3,416), as well as 19,993 controls. Cases and controls were matched by genotype array (i.e., Illumina array versions). Three case–control association studies each calculated and compared the observed vs. expected frequency of CNVs across individual genes, loci, pathways, and gene networks. Quality control measures of confidence in CNV-calling, prior to association analyses, included visual inspection of genotype and hybridization intensity. Results Here, we report results from CNV analysis in search for individual genes, loci, pathways, and gene networks. To extend our previous observations implicating a key role of the metabotropic glutamate receptor (mGluR) network in both ADHD and autism, we exhaustively queried patients with ASD and/or ADHD for CNVs associated with the 273 genomic regions of interest within the mGluR gene network (genes with one or two degrees protein–protein interaction with mGluR 1–8 genes). Among CNVs in mGluR network genes, we uncovered CNTN4 deletions enriched in NDD cases (P = 3.22E − 26, OR = 2.49). Additionally, we uncovered PRLHR deletions in 40 ADHD cases and 12 controls (P = 5.26E − 13, OR = 8.45) as well as clinically diagnostic relevant 22q11.2 duplications and 16p11.2 duplications in 23 ADHD + ASD cases and 9 controls (P = 4.08E − 13, OR = 15.05) and 22q11.2 duplications in 34 ADHD + ASD cases and 51 controls (P = 9.21E − 9, OR = 3.93); those control samples were not with previous 22qDS diagnosis in their EHR records. Conclusion Together, these results suggest that disruption in neuronal cell-adhesion pathways confers significant risk to NDDs and showcase that rare recurrent CNVs in CNTN4, 22q11.2, and 16p11.2 are overrepresented in NDDs that constitute patients predominantly suffering from ADHD and ASD. Trial registration ClinicalTrials.gov Identifier: NCT02286817 First Posted: 10 November 14, ClinicalTrials.gov Identifier: NCT02777931 first posted: 19 May 2016, ClinicalTrials.gov Identifier: NCT03006367 first posted: 30 December 2016, ClinicalTrials.gov Identifier: NCT02895906 first posted: 12 September 2016.

Abstract—In our previous experiments, it was found that the nootropic drugs piracetam (200 mg/kg/day, intraperitoneally), pantogam (100), pantogam active (200), phenibut (70), and semax (0.6), as well as a new derivative of racetam GIZh-290 (3), and the comparison drug atomoxetine (3.0), under subchronic administration restore attention stability to new objects in the "closed enriched cross maze" test, showing selectivity of the effect in relation to a subpopulation of CD-1 mice with an initially low attention index (ED-Low). In this study, the effect of nootropics on metabotropic glutamate receptors (mGluRII) in the prefrontal cortex of these mice was studied using the receptor binding of a specific radioligand [G-3H]LY354740. It was found that the density (Bmax) of mGluII receptors in the brains of subpopulation with the ED-Low phenotype was 11–25% lower than in subpopulation with the ED-High phenotype. None of the drugs had an effect on these receptors in the subpopulation with the ED-High phenotype, whereas phenibut, semax, and GIZh-290 showed efficacy in the ED-Low phenotype, increasing Bmax values by 60, 19, and 22%, respectively. Thus, it was shown for the first time that mGluRII are involved in the pathogenesis of attention impairment, and the ability of phenibut, semax, and GIZh-290 (2,6-dimethylanilide (2-oxo-4-phenylpyrrolidine-1-yl) acetate to selectively normalize the reduced density of these receptors indicates the prospects of their use as drugs for the treatment of attention deficit disorder. [ABSTRACT FROM AUTHOR]

Many mutations in autism spectrum disorder (ASD) affect a single allele, indicating a key role for gene dosage in ASD susceptibility. Recently, haplo-insufficiency of ITGB3, the gene encoding the extracellular matrix receptor β3 integrin, was associated with ASD. Accordingly, Itgb3 knockout (KO) mice exhibit autism-like phenotypes. The pathophysiological mechanisms of Itgb3 remain, however, unknown, and the potential of targeting this gene for developing ASD therapies uninvestigated. By combining molecular, biochemical, imaging, and pharmacological analyses, we establish that Itgb3 haplo-insufficiency impairs cortical network excitability by promoting extra-synaptic over synaptic signaling of the metabotropic glutamate receptor mGluR5, which is similarly dysregulated in fragile X syndrome, the most frequent monogenic form of ASD. To assess the therapeutic potential of regulating Itgb3 gene dosage, we implemented CRISPR activation and compared its efficacy with that of a pharmacological rescue strategy for fragile X syndrome. Correction of neuronal Itgb3 haplo-insufficiency by CRISPR activation rebalanced network excitability as effectively as blockade of mGluR5 with the selective antagonist MPEP. Our findings reveal an unexpected functional interaction between two ASD genes, thereby validating the pathogenicity of ITGB3 haplo-insufficiency. Further, they pave the way for exploiting CRISPR activation as gene therapy for normalizing gene dosage and network excitability in ASD.

Background: Neurodevelopmental disorders (NDDs), such as attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), are examples of complex and partially overlapping phenotypes that often lack definitive corroborating genetic information. ADHD and ASD have complex genetic associations implicated by rare recurrent copy number variations (CNVs). Both of these NDDs have been shown to share similar biological etiologies as well as genetic pleiotropy. Methods: Platforms aimed at investigating genetic-based associations, such as high-density microarray technologies, have been groundbreaking techniques in the field of complex diseases, aimed at elucidating the underlying disease biology. Previous studies have uncovered CNVs associated with genes within shared candidate genomic networks, including glutamate receptor genes, across multiple different NDDs. To examine shared biological pathways across two of the most common NDDs, we investigated CNVs across 15,689 individuals with ADHD (n = 7920), ASD (n = 4318), or both (n = 3,416), as well as 19,993 controls. Cases and controls were matched by genotype array (i.e., Illumina array versions). Three case–control association studies each calculated and compared the observed vs. expected frequency of CNVs across individual genes, loci, pathways, and gene networks. Quality control measures of confidence in CNV-calling, prior to association analyses, included visual inspection of genotype and hybridization intensity. Results: Here, we report results from CNV analysis in search for individual genes, loci, pathways, and gene networks. To extend our previous observations implicating a key role of the metabotropic glutamate receptor (mGluR) network in both ADHD and autism, we exhaustively queried patients with ASD and/or ADHD for CNVs associated with the 273 genomic regions of interest within the mGluR gene network (genes with one or two degrees protein–protein interaction with mGluR 1–8 genes). Among CNVs in mGluR network genes, we uncovered CNTN4 deletions enriched in NDD cases (P = 3.22E − 26, OR = 2.49). Additionally, we uncovered PRLHR deletions in 40 ADHD cases and 12 controls (P = 5.26E − 13, OR = 8.45) as well as clinically diagnostic relevant 22q11.2 duplications and 16p11.2 duplications in 23 ADHD + ASD cases and 9 controls (P = 4.08E − 13, OR = 15.05) and 22q11.2 duplications in 34 ADHD + ASD cases and 51 controls (P = 9.21E − 9, OR = 3.93); those control samples were not with previous 22qDS diagnosis in their EHR records. Conclusion: Together, these results suggest that disruption in neuronal cell-adhesion pathways confers significant risk to NDDs and showcase that rare recurrent CNVs in CNTN4, 22q11.2, and 16p11.2 are overrepresented in NDDs that constitute patients predominantly suffering from ADHD and ASD. Trial registration: ClinicalTrials.gov Identifier: NCT02286817 First Posted: 10 November 14, ClinicalTrials.gov Identifier: NCT02777931 first posted: 19 May 2016, ClinicalTrials.gov Identifier: NCT03006367 first posted: 30 December 2016, ClinicalTrials.gov Identifier: NCT02895906 first posted: 12 September 2016. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Glutamate is the major excitatory neurotransmitter in the central nervous system, and there is evidence that Group-I metabotropic glutamate receptors (mGlu1 and mGlu5) have established roles in excitatory neurotransmission and synaptic plasticity. While glutamate is abundantly present in the gut, it plays a smaller role in neurotransmission in the enteric nervous system. In this study, we examined the roles of Group-I mGlu receptors in gastrointestinal function. We investigated the expression of Grm1 (mGlu1) and Grm5 (mGlu5) in the mouse myenteric plexus using RNAscope in situ hybridization. Live calcium imaging and motility analysis were performed on ex vivo preparations of the mouse colon. mGlu5 was found to play a role in excitatory enteric neurotransmission, as electrically-evoked calcium transients were sensitive to the mGlu5 antagonist MPEP. However, inhibition of mGlu5 activity did not affect colonic motor complexes (CMCs). Instead, inhibition of mGlu1 using BAY 36-7620 reduced CMC frequency but did not affect enteric neurotransmission. These data highlight complex roles for Group-I mGlu receptors in myenteric neuron activity and colonic function. [ABSTRACT FROM AUTHOR]

Diabetes causes macrovascular and microvascular complications such as peripheral neuropathy. Glutamate regulates insulin secretion in pancreatic β-cells, and its increased activity in the central nervous system is associated with peripheral neuropathy in animal models of diabetes. One strategy to modulate glutamatergic activity consists in the pharmacological manipulation of metabotropic glutamate receptors (mGluRs), which, compared to the ionotropic receptors, allow for a fine-tuning of neurotransmission that is compatible with therapeutic interventions. mGluRs are a family of eight G-protein coupled receptors classified into three groups (I-III) based on sequence homology, transduction mechanisms, and pharmacology. Activation of group II and III or inhibition of group I represents a strategy to counteract the glutamatergic hyperactivity associated with diabetic neuropathy. In this review article, we will discuss the role of glutamate receptors in the release of insulin and the development/treatment of diabetic neuropathy, with particular emphasis on their manipulation to prevent the glutamatergic hyperactivity associated with diabetic neuropathy. [ABSTRACT FROM AUTHOR]

Our previous study has verified that activation of group Ⅰ metabotropic glutamate receptors (mGluRⅠ) in the red nucleus (RN) facilitate the development of neuropathological pain. Here, we further discussed the functions and possible molecular mechanisms of red nucleus mGluR Ⅱ (mGluR2 and mGluR3) in the development of neuropathological pain induced by spared nerve injury (SNI). Our results showed that mGluR2 and mGluR3 both were constitutively expressed in the RN of normal rats. At 2 weeks post-SNI, the protein expression of mGluR2 rather than mGluR3 was significantly reduced in the RN contralateral to the nerve lesion. Injection of mGluR2/3 agonist LY379268 into the RN contralateral to the nerve injury at 2 weeks post-SNI significantly attenuated SNI-induced neuropathological pain, this effect was reversed by mGluR2/3 antagonist EGLU instead of selective mGluR3 antagonist β-NAAG. Intrarubral injection of LY379268 did not alter the PWT of contralateral hindpaw in normal rats, while intrarubral injection of EGLU rather than β-NAAG provoked a significant mechanical allodynia. Further studies indicated that the expressions of nociceptive factors TNF-α and IL-1β in the RN were enhanced at 2 weeks post-SNI. Intrarubral injection of LY379268 at 2 weeks post-SNI significantly suppressed the overexpressions of TNF-α and IL-1β, these effects were reversed by EGLU instead of β-NAAG. Intrarubral injection of LY379268 did not influence the protein expressions of TNF-α and IL-1β in normal rats, while intrarubral injection of EGLU rather than β-NAAG significantly boosted the expressions of TNF-α and IL-1β. These findings suggest that red nucleus mGluR2 but not mGluR3 mediates inhibitory effect in the development of SNI-induced neuropathological pain by suppressing the expressions of TNF-α and IL-1β. mGluR Ⅱ may be potential targets for drug development and clinical treatment of neuropathological pain. • Red nucleus (RN) mGluR2 but not mGluR3 is reduced in spared nerve injury rats. • RN mGluR2 but not mGluR3 activation inhibits the development of neuropathic pain. • RN mGluR2 inhibits neuropathic pain by suppressing the expression of TNF-α. • RN mGluR2 inhibits neuropathic pain by suppressing the expression of IL-1β. [ABSTRACT FROM AUTHOR]

Our previous study has identified that glutamate in the red nucleus (RN) facilitates the development of neuropathic pain through metabotropic glutamate receptors (mGluR). Here, we further explored the actions and possible molecular mechanisms of red nucleus mGluR Ⅰ (mGluR1 and mGluR5) in the development of neuropathic pain induced by spared nerve injury (SNI). Our data indicated that both mGluR1 and mGluR5 were constitutively expressed in the RN of normal rats. Two weeks after SNI, the expressions of mGluR1 and mGluR5 were significantly boosted in the RN contralateral to the nerve injury. Administration of mGluR1 antagonist LY367385 or mGluR5 antagonist MTEP to the RN contralateral to the nerve injury at 2 weeks post-SNI significantly ameliorated SNI-induced neuropathic pain. However, unilateral administration of mGluRⅠ agonist DHPG to the RN of normal rats provoked a significant mechanical allodynia, this effect could be blocked by LY367385 or MTEP. Further studies indicated that the expressions of TNF-α and IL-1β in the RN were also elevated at 2 weeks post-SNI. Administration of mGluR1 antagonist LY367385 or mGluR5 antagonist MTEP to the RN at 2 weeks post-SNI significantly inhibited the elevations of TNF-α and IL-1β. However, administration of mGluR Ⅰ agonist DHPG to the RN of normal rats significantly enhanced the expressions of TNF-α and IL-1β, these effects were blocked by LY367385 or MTEP. These results suggest that activation of red nucleus mGluR1 and mGluR5 facilitate the development of neuropathic pain by stimulating the expressions of TNF-α and IL-1β. mGluR Ⅰ maybe potential targets for drug development and clinical treatment of neuropathic pain. • Enhanced mGluR1and mGluR5 in the red nucleus (RN) of spared nerve injury rats. • Activation of RN mGluR1and mGluR5 facilitate the development of neuropathic pain. • RN mGluR1and mGluR5 facilitate neuropathic pain by stimulating TNF-α expression. • RN mGluR1and mGluR5 facilitate neuropathic pain by stimulating IL-1β expression. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose : Modern neuroimaging lacks the tools necessary for whole-brain, anatomically dense neuronal damage screening. An ideal approach would include unbiased histopathologic identification of aging and neurodegenerative disease. Methods: We report the postmortem application of multiscale X-ray phase-contrast computed tomography (X-PCI-CT) for the label-free and dissection-free organ-level to intracellular-level 3D visualization of distinct single neurons and glia. In deep neuronal populations in the brain of aged wild-type and of 3xTgAD mice (a triply-transgenic model of Alzheimer's disease), we quantified intracellular hyperdensity, a manifestation of aging or neurodegeneration. Results: In 3xTgAD mice, the observed hyperdensity was identified as amyloid-β and hyper-phosphorylated tau protein deposits with calcium and iron involvement, by correlating the X-PCI-CT data to immunohistochemistry, X-ray fluorescence microscopy, high-field MRI, and TEM. As a proof-of-concept, X-PCI-CT was used to analyze hippocampal and cortical brain regions of 3xTgAD mice treated with LY379268, selective agonist of group II metabotropic glutamate receptors (mGlu2/3 receptors). Chronic pharmacologic activation of mGlu2/3 receptors significantly reduced the hyperdensity particle load in the ventral cortical regions of 3xTgAD mice, suggesting a neuroprotective effect with locoregional efficacy. Conclusions: This multiscale micro-to-nano 3D imaging method based on X-PCI-CT enabled identification and quantification of cellular and sub-cellular aging and neurodegeneration in deep neuronal and glial cell populations in a transgenic model of Alzheimer's disease. This approach quantified the localized and intracellular neuroprotective effects of pharmacological activation of mGlu2/3 receptors. [ABSTRACT FROM AUTHOR]

We studied the effect of lamotrigine, an anticonvulsant inhibiting the presynaptic release of glutamate, and LY341495, an antagonist of metabotropic glutamate 2/3 receptors, on the development of hyperthermic seizures and the content of LPO products in the brain of 8-10-day-old Wistar rats. Rat pups in the early postnatal period demonstrated pronounced seizures in response to thermal exposure, which was accompanied by an increase in the level of LPO products in the cerebral cortex. It was shown that the latency of generalized seizures increased after administration of both lamotrigine and LY341495. The most pronounced effect was observed in animals treated with lamotrigine. Both test substances prevented LPO intensification induced by hyperthermic exposure to varying degrees. [ABSTRACT FROM AUTHOR]

Metabotropic glutamate receptors (mGluRs) are G-protein coupled receptors that are activated by glutamate in the central nervous system (CNS). Basically, mGluRs contribute to fine-tuning of synaptic efficacy and control the accuracy and sharpness of neurotransmission. Among eight subtypes, mGluR1 and mGluR5 belong to group 1 (Gp1) family, and are implicated in multiple CNS disorders, such as Alzheimer's disease, autism, Parkinson's disease, and so on. In the present review, we systematically discussed underlying mechanisms and prospective of Gp1 mGluRs in a group of neurological and psychiatric diseases, including Alzheimer's disease, Parkinson's disease, autism spectrum disorder, epilepsy, Huntington's disease, intellectual disability, Down's syndrome, Rett syndrome, attention-deficit hyperactivity disorder, addiction, anxiety, nociception, schizophrenia, and depression, in order to provide more insights into the therapeutic potential of Gp1 mGluRs. [ABSTRACT FROM AUTHOR]

Recently we identified a deficiency in metabotropic glutamate receptor 2 (mGlu2) function in the corticoaccumbal pathway, as a common pathological mechanism underlying alcohol-seeking and relapse behavior. Based on this mechanism, we hypothesized that mGlu2/3 agonists and mGlu2 positive allosteric modulators (PAMs) may be effective in reducing relapse-like behavior. Two mGlu2/3 agonists, LY379268 and LY354740 (a structural analog of LY379268 six-fold more potent in activating mGlu2 over mGluR3), were tested in a well-established rat model of relapse, the alcohol deprivation effect (ADE) with repeated deprivation phases. Since these agonists do not readily discriminate between contributions of mGlu2 and mGluR3, we also tested LY487379, a highly specific PAM that potentiates the effect of glutamate on the mGlu2 with less specificity on other mGlu receptor subtypes. Both LY379268 and LY354740 significantly and dose-dependently reduced the expression of the ADE. No significant changes in water intake, body weight and locomotor activity were observed. Importantly, repeated administration of mGlu2/3 agonist did not lead to tolerance development. mGlu2 PAM LY487379 treatment significantly reduced expression of the ADE in both male and female rats. Combination treatment of mGlu2/3 agonist and PAM had similar effect on relapse-like drinking to that seen in mGlu2/3 agonist treatment alone. Together with other preclinical data showing that PAMs can reduce alcohol-seeking behavior we conclude that mGlu2 PAMs should be considered for clinical trials in alcohol-dependent patients. [ABSTRACT FROM AUTHOR]

Recently we identified a deficiency in metabotropic glutamate receptor 2 (mGlu2) function in the corticoaccumbal pathway, as a common pathological mechanism underlying alcohol-seeking and relapse behavior. Based on this mechanism, we hypothesized that mGlu2/3 agonists and mGlu2 positive allosteric modulators (PAMs) may be effective in reducing relapse-like behavior. Two mGlu2/3 agonists, LY379268 and LY354740 (a structural analog of LY379268 six-fold more potent in activating mGlu2 over mGluR3), were tested in a well-established rat model of relapse, the alcohol deprivation effect (ADE) with repeated deprivation phases. Since these agonists do not readily discriminate between contributions of mGlu2 and mGluR3, we also tested LY487379, a highly specific PAM that potentiates the effect of glutamate on the mGlu2 with less specificity on other mGlu receptor subtypes. Both LY379268 and LY354740 significantly and dose-dependently reduced the expression of the ADE. No significant changes in water intake, body weight and locomotor activity were observed. Importantly, repeated administration of mGlu2/3 agonist did not lead to tolerance development. mGlu2 PAM LY487379 treatment significantly reduced expression of the ADE in both male and female rats. Combination treatment of mGlu2/3 agonist and PAM had similar effect on relapse-like drinking to that seen in mGlu2/3 agonist treatment alone. Together with other preclinical data showing that PAMs can reduce alcohol-seeking behavior we conclude that mGlu2 PAMs should be considered for clinical trials in alcohol-dependent patients.

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.

Background and Purpose: As the thalamus underpins almost all aspects of behaviour, it is important to understand how the thalamus operates. Group II metabotropic glutamate (mGlu2/mGlu3) receptor activation reduces inhibition in thalamic nuclei originating from the surrounding thalamic reticular nucleus (TRN). Whilst an mGlu2 component to this effect has been reported, in this study, we demonstrate that it is likely, largely mediated via mGlu3. Experimental Approach The somatosensory ventrobasal thalamus (VB) is an established model for probing fundamental principles of thalamic function. In vitro slices conserving VB–TRN circuitry from wild‐type and mGlu3 knockout mouse brains were used to record IPSPs and mIPSCs. In vivo extracellular recordings were made from VB neurons in anaesthetised rats. A range of selective pharmacological agents were used to probe Group II mGlu receptor function (agonist, LY354740; antagonist, LY341495; mGlu2 positive allosteric modulator, LY487379 and mixed mGlu2 agonist/mGlu3 antagonist LY395756). Key Results: The in vitro and in vivo data are complementary and suggest that mGlu3 receptor activation is largely responsible for potentiating responses to somatosensory stimulation by reducing inhibition from the TRN. Conclusions and Implications: mGlu3 receptor activation in the VB likely enables important somatosensory information to be discerned from background activity. These mGlu3 receptors are likely to be endogenously activated via 'glutamate spillover'. In cognitive thalamic nuclei, this mechanism may be of importance in governing attentional processes. Positive allosteric modulation of endogenous mGlu3 receptor activation may therefore enhance cognitive function in pathophysiological disease states, such as schizophrenia, thus representing a highly specific therapeutic target. LINKED ARTICLES: This article is part of a themed issue on Building Bridges in Neuropharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.8/issuetoc [ABSTRACT FROM AUTHOR]

Abstract: Group I metabotropic glutamate receptors (group I mGluRs) have been implicated in several central nervous system diseases including chronic pain. It is known that activation of group I mGluRs results in the production of inositol triphosphate (IP3) and diacylglycerol that leads to activation of extracellular signal-regulated kinases (ERKs) and an increase in neuronal excitability, but how group I mGluRs mediate this process remains unclear. We previously reported that Orai1 is responsible for store-operated calcium entry and plays a key role in central sensitization. However, how Orai1 is activated under physiological conditions is unknown. Here, we tested the hypothesis that group I mGluRs recruit Orai1 as part of its downstream signaling pathway in dorsal horn neurons. We demonstrate that neurotransmitter glutamate induces STIM1 puncta formation, which is not mediated by N-Methyl-D-aspartate (NMDA) or α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Glutamate-induced Ca2+ entry in the presence of NMDA or AMPA receptor antagonists is eliminated in Orai1-deficient neurons. Dihydroxyphenylglycine (DHPG) (an agonist of group I mGluRs)-induced Ca2+ entry is abolished by Orai1 deficiency, but not affected by knocking down of transient receptor potential cation channel 1 (TRPC1) or TRPC3. Dihydroxyphenylglycine-induced activation of ERKs and modulation of neuronal excitability are abolished in cultured Orai1-deficient neurons. Moreover, DHPG-induced nociceptive behavior is markedly reduced in Orai1-deficient mice. Our findings reveal previously unknown functional coupling between Orai1 and group I mGluRs and shed light on the mechanism underlying group I mGluRs-mediated neuronal plasticity. [ABSTRACT FROM AUTHOR]

Metabotropic glutamate receptors (mGluRs; members of class C G-protein-coupled receptors) have been shown to modulate excitatory neurotransmission, regulate presynaptic extracellular glutamate levels, and modulate postsynaptic ion channels on dendritic spines. mGluRs were found to activate myriad signalling pathways to regulate synapse formation, long-term potentiation, autophagy, apoptosis, necroptosis, and pro-inflammatory cytokines release. A notorious expression pattern of mGluRs has been evident in several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and schizophrenia. Among the several mGluRs, mGluR5 is one of the most investigated types of considered prospective therapeutic targets and potential diagnostic tools in neurodegenerative diseases and neuropsychiatric disorders. Recent research showed mGluR5 radioligands could be a potential tool to assess neurodegenerative disease progression and trace respective drugs' kinetic properties. This article provides insight into the group I mGluRs, specifically mGluR5, in the progression and possible therapy for PD. [ABSTRACT FROM AUTHOR]

Glutamine, an excitatory neurotransmitter, is necessary for physiological as well as pathological processes. Other than neuronal disorders and/or cancers, glutamate receptors have also been associated with an array of other malignancies. The metabotropic glutamate receptor (mGluR 1–8 [like Groups I, II, and III]) and ionotropic glutamate receptor (iGluR) have been targeted to treat cancers like carcinoma of the lung, breast, prostate, and oral cancer. iGluRs present on N-methyl-D-aspartate (NMDA) and non-NMDA receptors are multisubunit complexes. Since these subunits of NMDA receptors influence the mTOR signaling pathway significantly, their antagonists such as memantine, ifenprodil, or diclozipine are often used in cancer chemotherapy. Non-NMDA receptors such as α-amino 3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) and kainate undergo glutamine to arginine site-specific RNA editing inflicting changes in cancer cell permeability. Thus, the employment of antagonists specific to these receptors would provide an effective anticancer therapeutic approach. Since AMPA receptors and kainate receptors have a crucial role in neural development and other cellular processes, their contribution in tumorigenesis has been mainly recognized in brain tumors although their role in further cancers cannot be ruled out. Delta or orphan receptors are primarily classified based on sequence homology. The effect and activity of antagonists for metabotropic and iGluRs have been pointed out due to their remedial contribution in various tumors. This review also highlights the relation of a range of subunits to cancer and anticancer agents as curatives for future applications and investigations.

Group I mGluRs have diverse functions in some fundamental neuronal processes, including modulation of synaptic plasticity; and dysregulation of these receptors could lead to various neuropsychiatric disorders. Trafficking of Group I mGluRs plays critical roles in controlling the precise spatiotemporal localization and activity of these receptors, both of which contribute to proper downstream signaling. Using "molecular replacement" approach in hippocampal neurons derived from mice of both sexes, we demonstrate a critical role for the postsynaptic density protein Norbin in regulating the ligand-induced internalization of Group I mGluRs. We show that Norbin associates with protein kinase A (PKA) through its N-terminus and anchors mGluR5 through its C-terminus, both of which are necessary for the ligand-mediated endocytosis of mGluR5, a member of the Group I mGluR family. A point mutation (A687G) at the C-terminus of Norbin inhibits the binding of Norbin to mGluR5 and blocks mGluR5 endocytosis. Finally, we demonstrate an important mechanism by which Norbin regulates mGluR-mediated AMPAR endocytosis in hippocampal neurons, a cellular correlate for mGluR-dependent synaptic plasticity. Norbin, through its PKA-binding regions, recruits PKA to AMPARs on activation of mGluRs; and deletion of the PKA-binding regions of Norbin inhibits mGluR-triggered AMPAR endocytosis. We further report that Norbin is important specifically for the mGluR-mediated AMPAR endocytosis, but not for NMDAR-dependent AMPAR endocytosis. Thus, this study unravels a novel role for Norbin in the internalization of mGluRs and mGluR-mediated AMPAR endocytosis that can have clinical relevance to the function of Group I mGluRs in pathologic processes. [ABSTRACT FROM AUTHOR]

The cellular mechanisms regulating dopamine (DA) release in the striatum have attracted much interest in recent years. By in vitro amperometric recordings in mouse striatal slices, we show that a brief (5 min) exposure to the metabotropic glutamate receptor agonist DHPG (50 μM) induces a profound depression of synaptic DA release, lasting over 1 h from DHPG washout. This long-term depression is sensitive to glycine, which preferentially inhibits local cholinergic interneurons, as well as to drugs acting on nicotinic acetylcholine receptors and to the pharmacological depletion of released acetylcholine. The same DHPG treatment induces a parallel long-lasting enhancement in the tonic firing of presumed striatal cholinergic interneurons, measured with multi-electrode array recordings. When DHPG is bilaterally infused in vivo in the mouse striatum, treated mice display an anxiety-like behavior. Our results demonstrate that metabotropic glutamate receptors stimulation gives rise to a prolonged depression of the striatal dopaminergic transmission, through a sustained enhancement of released acetylcholine, due to the parallel long-lasting potentiation of striatal cholinergic interneurons firing. This plastic interplay between dopamine, acetylcholine, and glutamate in the dorsal striatum may be involved in anxiety-like behavior typical of several neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

In the peripheral nervous system, the vast majority of axons are accommodated within the fibre bundles that constitute the peripheral nerves. Axons within the nerves are in close contact with myelinating glia, the Schwann cells that are ideally placed to respond to, and possibly shape, axonal activity. The mechanisms of intercellular communication in the peripheral nerves may involve direct contact between the cells, as well as signalling via diffusible substances. Neurotransmitter glutamate has been proposed as a candidate extracellular molecule mediating the cross-talk between cells in the peripheral nerves. Two types of experimental findings support this idea: first, glutamate has been detected in the nerves and can be released upon electrical or chemical stimulation of the nerves; second, axons and Schwann cells in the peripheral nerves express glutamate receptors. Yet, the studies providing direct experimental evidence that intercellular glutamatergic signalling takes place in the peripheral nerves during physiological or pathological conditions are largely missing. Remarkably, in the central nervous system, axons and myelinating glia are involved in glutamatergic signalling. This signalling occurs via different mechanisms, the most intriguing of which is fast synaptic communication between axons and oligodendrocyte precursor cells. Glutamate receptors and/or synaptic axon-glia signalling are involved in regulation of proliferation, migration, and differentiation of oligodendrocyte precursor cells, survival of oligodendrocytes, and re-myelination of axons after damage. Does synaptic signalling exist between axons and Schwann cells in the peripheral nerves? What is the functional role of glutamate receptors in the peripheral nerves? Is activation of glutamate receptors in the nerves beneficial or harmful during diseases? In this review, we summarise the limited information regarding glutamate release and glutamate receptors in the peripheral nerves and speculate about possible mechanisms of glutamatergic signalling in the nerves. We highlight the necessity of further research on this topic because it should help to understand the mechanisms of peripheral nervous system development and nerve regeneration during diseases.

Glutamate is the major excitatory neurotransmitter in the central nervous system, and there is evidence that Group-I metabotropic glutamate receptors (mGlu1 and mGlu5) have established roles in excitatory neurotransmission and synaptic plasticity. While glutamate is abundantly present in the gut, it plays a smaller role in neurotransmission in the enteric nervous system. In this study, we examined the roles of Group-I mGlu receptors in gastrointestinal function. We investigated the expression of Grm1 (mGlu1) and Grm5 (mGlu5) in the mouse myenteric plexus using RNAscope in situ hybridization. Live calcium imaging and motility analysis were performed on ex vivo preparations of the mouse colon. mGlu5 was found to play a role in excitatory enteric neurotransmission, as electrically-evoked calcium transients were sensitive to the mGlu5 antagonist MPEP. However, inhibition of mGlu5 activity did not affect colonic motor complexes (CMCs). Instead, inhibition of mGlu1 using BAY 36-7620 reduced CMC frequency but did not affect enteric neurotransmission. These data highlight complex roles for Group-I mGlu receptors in myenteric neuron activity and colonic function.

This overview describes how group mGluR1/5 metabotropic glutamate receptors are involved in neurodegenerative diseases; it also touches upon their use as therapeutic targets in animal models. mGluR1/5 are primarily located on the neuronal postsynaptic membrane, where they communicate with two proteins, Gq/11 and Homer, which, in turn, initiate several biochemical cascades. The Gq/11 protein cascade includes Са2+ release from the endoplasmic reticulum (ER) through the inositol trisphosphate receptors (IP3R) and the activation of depot-controlled Са2+ entry. The Gq/11 protein cascade also includes the production of diacylglycerol with subsequent activation of various protein kinases, which, in turn, provide influences on the genome. The Homer protein communicates directly with the NMDA receptors and Shank scaffold proteins, through which it regulates the activity of various protein kinases, including Akt and ERK1/2. The activation of mGluR1/5 triggers long-term depression of glutamatergic transmission through the endocytosis of AMPA receptors, caused by changes in the level of protein phosphorylation and genome activation. It is thought that mGluR1/5 play an important role in the development of neurodegenerative diseases. In Alzheimer's disease, mGluR1/5 acts as a target for the -amyloid peptide. mGluR1/5 antagonists have a neuroprotective effect in transgenic mice with Alzheimer's disease. The pathogenesis of Alzheimer's disease includes increased Са2+ release from the ER due to the pathological activity of mGluR1/5, as well as the influence of mutated presenilin on Са2+ homeostasis in the ER. At the same time, restoration of Са2+ levels in the ER is disrupted by the effect of presenilin on depot-activated Са2+ entry. mGluR5 (but not mGluR1) is being studied as a potential therapeutic target in Parkinson's disease. Numerous studies on rodent and primate models of Parkinson's disease have demonstrated a significant antiparkinsonian effect when mGluR5 antagonists were used. It is thought that the neuroprotective mechanisms of action of mGluR5 antagonists involve limiting the increase in intracellular Са2+ by reducing IP3 and NMDA receptor activation. Huntingtons disease is related to a mutation in the HTT gene and the ability of the mutant huntingtin protein to sensitise IP3 and NMDA receptors, thus triggering Са2+ overload in the neurons. A neuroprotective effect in transgenic mice with Huntingtons disease was achieved by using positive allosteric modulators of mGluR5, capable of selectively activating cascades associated with the Homer protein and triggering Akt activation.

The cellular mechanisms regulating dopamine (DA) release in the striatum have attracted much interest in recent years. By in vitro amperometric recordings in mouse striatal slices, we show that a brief (5 min) exposure to the metabotropic glutamate receptor agonist DHPG (50 μM) induces a profound depression of synaptic DA release, lasting over 1 h from DHPG washout. This long-term depression is sensitive to glycine, which preferentially inhibits local cholinergic interneurons, as well as to drugs acting on nicotinic acetylcholine receptors and to the pharmacological depletion of released acetylcholine. The same DHPG treatment induces a parallel long-lasting enhancement in the tonic firing of presumed striatal cholinergic interneurons, measured with multi-electrode array recordings. When DHPG is bilaterally infused in vivo in the mouse striatum, treated mice display an anxiety-like behavior. Our results demonstrate that metabotropic glutamate receptors stimulation gives rise to a prolonged depression of the striatal dopaminergic transmission, through a sustained enhancement of released acetylcholine, due to the parallel long-lasting potentiation of striatal cholinergic interneurons firing. This plastic interplay between dopamine, acetylcholine, and glutamate in the dorsal striatum may be involved in anxiety-like behavior typical of several neuropsychiatric disorders.

Cognitive dysfunction is associated with methamphetamine use disorder (MUD). Here, we used genetic and pharmacological approaches to examine the involvement of either Group 2 metabotropic glutamate (mGlu2) or mGlu3 receptors in memory deficit induced by methamphetamine in mice. Methamphetamine treatment (1 mg/kg, i.p., once a day for 5 d followed by 7 d of withdrawal) caused an impaired performance in the novel object recognition test in wild-type mice, but not in mGlu2 -/- or mGlu3 -/- mice. Memory deficit in wild-type mice challenged with methamphetamine was corrected by systemic treatment with selectively negative allosteric modulators of mGlu2 or mGlu3 receptors (compounds VU6001966 and VU0650786, respectively). Methamphetamine treatment in wild-type mice caused large increases in levels of mGlu2/3 receptors, the Type 3 activator of G-protein signaling (AGS3), Rab3A, and the vesicular glutamate transporter, vGlut1, in the prefrontal cortex (PFC). Methamphetamine did not alter mGlu2/3-mediated inhibition of cAMP formation but abolished the ability of postsynaptic mGlu3 receptors to boost mGlu5 receptor-mediated inositol phospholipid hydrolysis in PFC slices. Remarkably, activation of presynaptic mGlu2/3 receptors did not inhibit but rather amplified depolarization-induced [ 3 H]-D-aspartate release in synaptosomes prepared from the PFC of methamphetamine-treated mice. These findings demonstrate that exposure to methamphetamine causes changes in the expression and function of mGlu2 and mGlu3 receptors, which might alter excitatory synaptic transmission in the PFC and raise the attractive possibility that selective inhibitors of mGlu2 or mGlu3 receptors (or both) may be used to improve cognitive dysfunction in individuals affected by MUD., (Copyright © 2024 Busceti et al.)

Identified 40 years ago, the metabotropic glutamate (mGlu) receptors play key roles in modulating many synapses in the brain, and are still considered as important drug targets to treat various brain diseases. Eight genes encoding mGlu subunits have been identified. They code for complex receptors composed of a large extracellular domain where glutamate binds, connected to a G protein activating membrane domain. They are covalently linked dimers, a quaternary structure needed for their activation by glutamate. For many years they have only been considered as homodimers, then limiting the number of mGlu receptors to 8 subtypes composed of twice the same subunit. Twelve years ago, mGlu subunits were shown to also form heterodimers with specific subunits combinations, increasing the family up to 19 different potential dimeric receptors. Since then, a number of studies brought evidence for the existence of such heterodimers in the brain, through various approaches. Structural and molecular dynamic studies helped understand their peculiar activation process. The present review summarizes the approaches used to study their activation process and their pharmacological properties and to demonstrate their existence in vivo. We will highlight how the existence of mGlu heterodimers revolutionizes the mGlu receptor field, opening new possibilities for therapeutic intervention for brain diseases. As illustrated by the number of possible mGlu heterodimers, this study will highlight the need for further research to fully understand their role in physiological and pathological conditions, and to develop more specific therapeutic tools., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Overdose death rates caused by psychostimulants have increased by 22.3% annually from 2008 to 2017. Cue‐evoked drug craving progressively increases and contributes to perpetual relapse. Preclinical models have determined that glutamate receptor plasticity within the nucleus accumbens (NAc) drives amplified cue‐evoked drug seeking after prolonged abstinence (>40 days). Isolated condition (IC) rearing increases cocaine and amphetamine (AMP) self‐administration and cue‐induced reinstatement. We tested the hypothesis that housing in the IC will augment AMP seeking after short and prolonged abstinence from AMP self‐administration when compared with rats reared in the enrichment condition (EC). EC and IC male rats acquired stable AMP or SAL self‐administration and were tested in a cue‐induced AMP‐seeking test after 1 and 40 days of abstinence. After the seeking test, the whole NAc was extracted and prepared for western blot analysis. Results indicate that IC rats had more active lever presses during a brief extinction interval and during the cue‐induced seeking test. After 40 days of abstinence, IC rats had more active lever presses than EC rats during the cue‐induced seeking test. Western blots indicated that the expression ratio between GluA1:mGlur5 was reduced only in IC‐AMP‐trained rats and the ratio between GluA1:mGlur1 was positively correlated with AMP seeking after prolonged abstinence in IC‐AMP rats. These results indicate that IC housing engenders a vulnerable phenotype prone to persistent AMP seeking. The behavioural momentum of this vulnerable phenotype is further revealed when AMP‐associated cues are presented following prolonged abstinence. [ABSTRACT FROM AUTHOR]

Addiction results from drug-elicited alterations of synaptic plasticity mechanisms in dopaminergic reward circuits. Impaired metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) and accumulation of synaptic Ca2+-permeable AMPA receptors (CP-AMPARs) following drug exposure have emerged as important mechanisms underlying drug craving and relapse. Here we show that repeated cocaine exposure in vivo causes transient but complete loss of mGluR1- and mTOR (mammalian target of rapamycin)-dependent LTD in layer 5 pyramidal neurons of mouse prefrontal cortex (PFC), a major dopaminergic target in the reward circuitry. This mGluR1-LTD impairment was prevented by in vivo administration of an mGluR1 positive allosteric modulator (PAM) and rescued by inhibition of dopamine D1 receptors, suggesting that impaired mGluR1 tone and excessive D1 signaling underlie this LTD deficit. Concurrently, CP-AMPARs were generated, indicated by increased sensitivity to the CP-AMPAR inhibitor Naspm and rectification of synaptic AMPAR currents, which were reversed by PAM in cocaine-exposed mice. Finally, these CP-AMPARs mediate an abnormal spike-timing-dependent long-term potentiation enabled by cocaine exposure. Our findings reveal a mechanism by which cocaine impairs LTD and remodels synaptic AMPARs to influence Hebbian plasticity in the PFC. Failure to undergo LTD may prevent the reversal of drug-potentiated brain circuits to their baseline states, perpetuating addictive behaviors. A mGluR1- and mTOR-dependent LTD is present in the mouse medial prefrontal cortex. Repeated cocaine exposure in vivo temporally but completely abolishes prefrontal mGluR1-LTD. Impaired mGluR1 function and excessive D1 DA signaling likely underlie cocaine impairment of mGluR1-LTD. Ca2+-permeable AMPA receptors are generated by cocaine exposure, likely resulting from mGluR1-LTD impairment, and contribute to a cocaine-induced extended spike timing LTP. [ABSTRACT FROM AUTHOR]

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.

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Stress negatively affects processes of synaptic plasticity and is a major risk factor of various psychopathologies such as depression and anxiety. HOMER1 is an important component of the postsynaptic density: constitutively expressed long isoforms HOMER1b and HOMER1c bind to group I metabotropic glutamate receptors MGLUR1 (GRM1) and MGLUR5 and to other effector proteins, thereby forming a postsynaptic protein scaffold. Activation of the GLUR1–HOMER1b,c and/or GLUR5–HOMER1b,c complex regulates activity of the NMDA and AMPA receptors and Ca2+ homeostasis, thus modulating various types of synaptic plasticity. Dominant negative transcript Homer1a is formed as a result of activity-induced alternative termination of transcription. Expression of this truncated isoform in response to neuronal activation impairs interactions of HOMER1b,c with adaptor proteins, triggers ligand-independent signal transduction through MGLUR1 and/or MGLUR5, leads to suppression of the AMPA- and NMDA-mediated signal transmission, and thereby launches remodeling of the postsynaptic protein scaffold and inhibits long-term potentiation. The studies on animal models confirm that the HOMER1a-dependent remodeling most likely plays an important part in the stress susceptibility, whereas HOMER1a itself can be regarded as a neuroprotector. In this review article, we consider the effects of different stressors in various animal models on HOMER1 expression as well as impact of different HOMER1 variants on human behavior as well as structural and functional characteristics of the brain. [ABSTRACT FROM AUTHOR]

Background: Sleep consolidates declarative memory by repeated replay linked to the cardinal oscillations of non-rapid eye movement (NonREM) sleep. However, there is so far little evidence of classical glutamatergic plasticity induced by this replay. Rather, we have previously reported that blocking N-methyl-D-aspartate (NMDA) or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors does not affect sleep-dependent consolidation of declarative memory. Aims: The aim of this study was to investigate the role of metabotropic glutamate receptor 5 (mGluR5) in memory processing during sleep. Methods: In two placebo-controlled within-subject crossover experiments with 20 healthy humans each, we used fenobam to block mGluR5 during sleep. In Experiment I, participants learned word-pairs (declarative task) and a finger sequence (procedural task) in the evening, then received the drug and recall was tested the next morning. To cover possible effects on synaptic renormalization processes during sleep, in Experiment II participants learned new word-pairs in the morning after sleep. Results/outcomes: Surprisingly, fenobam neither reduced retention of memory across sleep nor new learning after sleep, although it severely altered sleep architecture and memory-relevant EEG oscillations. In NonREM sleep, fenobam suppressed 12–15 Hz spindles but augmented 2–4 Hz delta waves, whereas in rapid eye movement (REM) sleep it suppressed 4–8 Hz theta and 16–22 Hz beta waves. Notably, under fenobam NonREM spindles became more consistently phase-coupled to the slow oscillation. Conclusions/interpretations: Our findings indicate that mGluR5-related plasticity is not essential for memory processing during sleep, even though mGlurR5 are strongly implicated in the regulation of the cardinal sleep oscillations. [ABSTRACT FROM AUTHOR]