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Nalmefene, an analog to naltrexone, is an antagonist at the μ opioid receptor and a partial agonist at the κ opioid receptor. Both agents are approved for the treatment of alcohol use disorder and opioid addiction. Here, we evaluated the potential of nalmefene for treating psychostimulant dependence using a methamphetamine (METH) self-administration rat model. Rats were trained to press a lever for 0.02-mg intravenous METH infusions paired with drug-associated cues (light and tone) under a fixed ratio 1 schedule. After a 10-day METH self-administration acquisition phase, rats underwent extinction training. A reinstatement test was conducted after fulfilment of the extinction criterion under saline infusions. Re-exposure to METH-associated cues or a priming injection of METH (1.0 mg/kg, i.p.) significantly reinstated METH-seeking behaviors. Pretreatment with nalmefene (10 mg/kg, i.p.) immediately before reinstatement tests significantly attenuated the METH-seeking behaviors induced by both cues and METH priming injection. To investigate the mechanism of effect of nalmefene, we also tested the ability of a group II metabotropic glutamate receptors (mGluR2/3) antagonist, LY341495, to the ameliorating effects of nalmefene. Pretreatment with LY341495 (1.0 mg/kg, i.p.) before nalmefene administration antagonized the effect of nalmefene on reinstatement. LY341495 alone did not affect the reinstatement of lever pressing. We found that nalmefene attenuates METH-seeking behaviors during withdrawal, and this attenuation of reinstatement is mediated by the activation of mGluR2/3. The present findings suggest that nalmefene could decrease incentive motivation for drug use in psychostimulant dependence., Competing Interests: Declaration of Competing Interest None of the authors declare any conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Glutamate, an excitatory neurotransmitter, is essential for neuronal function, and it acts on ionotropic or metabotropic glutamate receptors (mGluRs). A disturbance in glutamatergic signaling is a hallmark of many neurodegenerative diseases. Developing disease-modifying treatments for neurodegenerative diseases targeting glutamate receptors is a promising avenue. The understudied group III mGluR 4, 6-8 are commonly found in the presynaptic membrane, and their activation inhibits glutamate release. Thus, targeted mGluRs therapies could aid in treating neurodegenerative diseases. This review describes group III mGluRs and their pharmacological ligands in the context of amyotrophic lateral sclerosis, Parkinson's, Alzheimer's, and Huntington's diseases. Attempts to evaluate the efficacy of these drugs in clinical trials are also discussed. Despite a growing list of group III mGluR-specific pharmacological ligands, research on the use of these drugs in neurodegenerative diseases is limited, except for Parkinson's disease. Future efforts should focus on delineating the contribution of group III mGluR to neurodegeneration and developing novel ligands with superior efficacy and a favorable side effect profile for the treatment of neurodegenerative diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Glutamate, the major excitatory neurotransmitter in the brain exerts its effects via both ionotropic glutamate receptors and metabotropic glutamate receptors (mGluRs). There are three subgroups of mGluRs, pre-synaptic Group II and Group III mGluRs and post-synaptic Group I mGluRs. mGluRs are ubiquitously expressed in the brain and their activation is poised upstream of a myriad of signaling pathways, resulting in their implication in the pathogenesis of various neurodegenerative diseases including, Alzheimer's Disease (AD). While the exact mechanism of AD etiology remains elusive, β-amyloid (Aβ) plaques and hyperphosphorylated tau tangles remain the histopathological hallmarks of AD. Though less electrically excitable, neuroglia are a major non-neuronal cell type in the brain and are composed of astrocytes, microglia, and oligodendrocytes. Astrocytes, microglia, and oligodendrocytes provide structural and metabolic support, active immune defence, and axonal support and sheathing, respectively. Interestingly, Aβ and hyperphosphorylated tau are known to disrupt the neuroglial homeostasis in the brain, pushing them towards a more neurotoxic state. In this review, we discuss what is currently known regarding the expression patterns of various mGluRs in neuroglia and how Aβ and tau alter the normal mGluR function in the neuroglia and contribute to the pathophysiology of AD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Alzheimer's disease (AD) was first identified more than 100 years ago, yet aspects pertaining to its origin and the mechanisms underlying disease progression are not well known. To this date, there is no therapeutic approach or disease-modifying drug that could halt or at least delay disease progression. Until recently, glial cells were seen as secondary actors in brain homeostasis. Although this view was gradually refuted and the relevance of glial cells for the most diverse brain functions such as synaptic plasticity and neurotransmission was vastly proved, many aspects of its functioning, as well as its role in pathological conditions, remain poorly understood. Metabotropic glutamate receptors (mGluRs) in glial cells were shown to be involved in neuroinflammation and neurotoxicity. Besides its relevance for glial function, glutamatergic receptors are also central in the pathology of AD, and recent studies have shown that glial mGluRs play a role in the establishment and progression of AD. AD-related alterations in Ca 2+ signalling, APP processing, and Aβ load, as well as AD-related neurodegeneration, are influenced by glial mGluRs. However, different types of mGluRs play different roles, depending on the cell type and brain region that is being analysed. Therefore, in this review, we focus on the current understanding of glial mGluRs and their implication in AD, providing an insight for future therapeutics and identifying existing research gaps worth investigating., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

On the occasion of the 40 year anniversary of the hugely impactful review by Richard (Dick) Evans and Jeff Watkins, we describe how their work has impacted the field of synaptic plasticity. We describe their influence in each of the major glutamate receptor subtypes: AMPARs, NMDARs, KARs and mGluRs. Particular emphasis is placed on how their work impacted our own studies in the hippocampus. For example, we describe how the tools and regulators that they identified for studying NMDARs (e.g., NMDA, D-AP5 and Mg 2+ ) led to the understanding of the molecular basis of the induction of LTP. We also describe how other tools that they introduced (e.g., (1S,3R)-ACPD and MCPG) helped lead to the concept of metaplasticity., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Metabotropic glutamate receptors (mGluRs) have been discovered almost four decades ago. Since then, their pharmacology has been largely developed as well as their structural organization. Indeed mGluRs are attractive therapeutic targets for numerous psychiatric and neurological disorders because of their modulating role of synaptic transmission. The more recent drug discovery programs have mostly concentrated on allosteric modulators. However, orthosteric agonists and antagonists have remained unavoidable pharmacological tools as, although not expected, many of them can reach the brain, or can be modified to reach the brain. This review focuses on the most common orthosteric ligands as well as on the few allosteric modulators interacting with the glutamate binding domain. The 3D-structures of these ligands at their binding sites are reported. For most of them, X-Ray structures or docked homology models are available. Because of the high conservation of the binding site, subtype selective agonists were not easy to find. Yet, some were discovered when extending their chemical structures in order to reach selective sites of the receptors., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Astroglial cells were long considered as structural and metabolic supporting cells are which do not directly participate in information processing in the brain. Discoveries of responsiveness of astrocytes to synaptically-released glutamate and their capability to release agonists of glutamate receptors awakened extensive studies of glia-neuron communications and led to the revolutionary changes in our understanding of brain cellular networks. Nowadays, astrocytes are widely acknowledged as inseparable element of glutamatergic synapses and role for glutamatergic astrocyte-neuron interactions in the brain computation is emerging. Astroglial glutamate receptors, in particular of NMDA, mGluR3 and mGluR5 types, can activate a variety of molecular cascades leading astroglial-driven modulation of extracellular levels of glutamate and activity of neuronal glutamate receptors. Their preferential location to the astroglial perisynaptic processes facilitates interaction of astrocytes with individual excitatory synapses. Bi-directional glutamatergic communication between astrocytes and neurons underpins a complex, spatially-distributed modulation of synaptic signalling thus contributing to the enrichment of information processing by the neuronal networks. Still, further research is needed to bridge the substantial gaps in our understanding of mechanisms and physiological relevance of astrocyte-neuron glutamatergic interactions, in particular ability of astrocytes directly activate neuronal glutamate receptors by releasing glutamate and, arguably, d-Serine. An emerging roles for aberrant changes in glutamatergic astroglial signalling, both neuroprotective and pathogenic, in neurological and neurodegenerative diseases also require further investigation. This article is part of the special Issue on 'Glutamate Receptors - The Glutamatergic Synapse'., (Copyright © 2021. Published by Elsevier Ltd.)

Degenerative diseases of the retina are responsible for the death of photoreceptors and subsequent loss of vision in patients. Nevertheless, the inner retinal layers remain intact over an extended period of time, enabling the restoration of light sensitivity in blind retinas via the expression of optogenetic tools in the remaining retinal cells. The chimeric Opto-mGluR6 protein represents such a tool. With exclusive ON-bipolar cell expression, it combines the light-sensitive domains of melanopsin and the intracellular domains of the metabotropic glutamate receptor 6 (mGluR6), which naturally mediates light responses in these cells. Albeit vision restoration in blind mice by Opto-mGluR6 delivery was previously shown, much is left to be explored in regard to the effects of the timing of the treatment in the degenerated retina. We performed a functional evaluation of Opto-mGluR6-treated murine blind retinas using multi-electrode arrays (MEAs) and observed long-term functional preservation in the treated retinas, as well as successful therapeutical intervention in later stages of degeneration. Moreover, the treatment decreased the inherent retinal hyperactivity of the degenerated retinas to levels undistinguishable from healthy controls. Finally, we observed for the first time micro electroretinograms (mERGs) in optogenetically treated animals, corroborating the origin of Opto-mGluR6 signalling at the level of mGluR6 of ON-bipolar cells.

Previous studies have demonstrated that brain-derived neurotrophic factor (BDNF) is one of the diffusible messengers for enhancing synaptic transmission in the hippocampus. Less information is available about the possible roles of BDNF in the anterior cingulate cortex (ACC). In the present study, we used 64-electrode array field recording system to investigate the effect of BDNF on ACC excitatory transmission. We found that BDNF enhanced synaptic responses in a dose-dependent manner in the ACC in C57/BL6 mice. The enhancement was long-lasting, and persisted for at least 3 h. In addition to the enhancement, BDNF also recruited inactive synaptic responses in the ACC. Bath application of the tropomyosin receptor kinase B (TrkB) receptor antagonist K252a blocked BDNF-induced enhancement. L-type voltage-gated calcium channels (L-VGCC), metabotropic glutamate receptors (mGluRs), but not NMDA receptors were required for BDNF-produced enhancement. Moreover, calcium-stimulated adenylyl cyclase subtype 1 (AC1) but not AC8 was essential for the enhancement. A selective AC1 inhibitor NB001 completely blocked the enhancement. Furthermore, BDNF-produced enhancement occluded theta burst stimulation (TBS) induced long-term potentiation (LTP), suggesting that they may share similar signaling mechanisms. Finally, the expression of BDNF-induced enhancement depends on postsynaptic incorporation of calcium-permeable AMPA receptors (CP-AMPARs) and protein kinase Mζ (PKMζ). Our results demonstrate that cortical BDNF may contribute to synaptic potentiation in the ACC., (© 2021. The Author(s).)

Enigmatic orphan glutamate delta receptors (GluD) are one of the four classes of the ionotropic glutamate receptors (iGluRs) that play key roles in synaptic transmission and plasticity. While members of other iGluR families viz AMPA, NMDA, and kainate receptors are gated by glutamate, the GluD receptors neither bind glutamate nor evoke ligand-induced currents upon binding of glycine and D-serine. Thus, the GluD receptors were considered to function as structural proteins that facilitate the formation, maturation, and maintenance of synapses in the hippocampus and cerebellum. Recent work has revealed that GluD receptors have extensive crosstalk with metabotropic glutamate receptors (mGlus) and are also gated by their activation. The latest development of a novel optopharamcological tool and the cryoEM structures of GluD receptors would help define the molecular and chemical basis of the GluD receptor's role in synaptic physiology. This article is part of the special Issue on "Glutamate Receptors - Orphan iGluRs"., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Hypoxic ischemic brain injury (HIBI) has been one of the most severe central nervous system (CNS) diseases with high fatality and disability rate. Neural stem cells (NSCs) persist in the mammalian brain throughout life and NSCs-associated therapies might be a promising strategy for the HIBI treatment. In this study, we identified that type 4 metabotropic glutamate receptor (mGluR4) was expressed in cultured human NSCs (hNSCs) isolated from the human fetus cortex and further established the oxygen and glucose deprivation (OGD) model in hNSCs to study the role of mGluR4 in hypoxic and ischemic injury. The results indicated that mGluR4 activation by using VU0155041 (mGluR4-specific agonist) markedly attenuated the OGD-induced alterations in TUNEL staining, apoptosis rate, cleavages of pro-caspase-8, -9, -3, and Bcl-2/Bax expression balance. Furthermore, mGluR4 activation inhibited the ASK1/p38 signaling pathway. Asiatic acid, as a p38 MAPK activator, is capable of abolishing the neuroprotective effect of mGluR4, while both NQDI-1 (ASK-1 inhibitor) and SB203580 (p38 MAPK inhibitor) exerted similar effects to VU0155041 in the OGD-induced hNSC damage. In conclusion, this study indicates that mGluR4 activation protects hNSCs against the OGD-induced cell death via inhibiting the ASK1-p38 pathway. Activation of mGluR4 might be a promising strategy for enhancing NSCs survival in hypoxic and ischemic injury., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is a progressive neurodegenerative disease marked by the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles. Aβ oligomers cause synaptic dysfunction early in AD by enhancing long-term depression (LTD; a paradigm for forgetfulness) via metabotropic glutamate receptor (mGluR)-dependent regulation of striatal-enriched tyrosine phosphatase (STEP 61 ). Reelin is a neuromodulator that signals through ApoE (apolipoprotein E) receptors to protect the synapse against Aβ toxicity (Durakoglugil et al., 2009) Reelin signaling is impaired by ApoE4, the most important genetic risk factor for AD, and Aβ-oligomers activate metabotropic glutamate receptors (Renner et al., 2010). We therefore asked whether Reelin might also affect mGluR-LTD. To this end, we induced chemical mGluR-LTD using DHPG (Dihydroxyphenylglycine), a selective mGluR5 agonist. We found that exogenous Reelin reduces the DHPG-induced increase in STEP 61 , prevents the dephosphorylation of GluA2, and concomitantly blocks mGluR-mediated LTD. By contrast, Reelin deficiency increased expression of Ca 2+ -permeable GluA2-lacking AMPA receptors along with higher STEP 61 levels, resulting in occlusion of DHPG-induced LTD in hippocampal CA1 neurons. We propose a model in which Reelin modulates local protein synthesis as well as AMPA receptor subunit composition through modulation of mGluR-mediated signaling with implications for memory consolidation or neurodegeneration. SIGNIFICANCE STATEMENT Reelin is an important neuromodulator, which in the adult brain controls synaptic plasticity and protects against neurodegeneration. Amyloid-β has been shown to use mGluRs to induce synaptic depression through endocytosis of NMDA and AMPA receptors, a mechanism referred to as LTD, a paradigm of forgetfulness. Our results show that Reelin regulates the phosphatase STEP, which plays an important role in neurodegeneration, as well as the expression of calcium-permeable AMPA receptors, which play a role in memory formation. These data suggest that Reelin uses mGluR LTD pathways to regulate memory formation as well as neurodegeneration., (Copyright © 2021 Durakoglugil et al.)

Somatostatin-expressing interneurons (SOM-INs) are a major subpopulation of GABAergic cells in CA1 hippocampus that receive excitation from pyramidal cells (PCs), and, in turn, provide feedback inhibition onto PC dendrites. Excitatory synapses onto SOM-INs show a Hebbian long-term potentiation (LTP) mediated by type 1a metabotropic glutamate receptors (mGluR1a) that is implicated in hippocampus-dependent learning. The neuropeptide somatostatin (SST) is also critical for hippocampal long-term synaptic plasticity, as well as learning and memory. SST effects on hippocampal PCs are well documented, but its actions on inhibitory interneurons remain largely undetermined. In the present work, we investigate the involvement of SST in long-term potentiation of CA1 SOM-IN excitatory synapses using pharmacological approaches targeting the somatostatinergic system and whole cell recordings in slices from transgenic mice expressing eYFP in SOM-INs. We report that application of exogenous SST 14 induces long-term potentiation of excitatory postsynaptic potentials in SOM-INs via somatostatin type 1-5 receptors (SST 1-5 Rs) but does not affect synapses of PC or parvalbumin-expressing interneurons. Hebbian LTP in SOM-INs was prevented by inhibition of SSTRs and by depletion of SST by cysteamine treatment, suggesting a critical role of endogenous SST in LTP. LTP of SOM-IN excitatory synapses induced by SST 14 was independent of NMDAR and mGluR1a, activity-dependent, and prevented by blocking GABA A receptor function. Our results indicate that endogenous SST may contribute to Hebbian LTP at excitatory synapses of SOM-INs by controlling GABA A inhibition, uncovering a novel role for SST in regulating long-term synaptic plasticity in somatostatinergic cells that may be important for hippocampus-dependent memory processes., (© 2021. The Author(s).)

Pathological impulsivity is a debilitating symptom of multiple psychiatric diseases with few effective treatment options. To identify druggable receptors with anti-impulsive action we developed a systematic target discovery approach combining behavioural chemogenetics and gene expression analysis. Spatially restricted inhibition of three subdivisions of the prefrontal cortex of mice revealed that the anterior cingulate cortex (ACC) regulates premature responding, a form of motor impulsivity. Probing three G-protein cascades with designer receptors, we found that the activation of G i -signalling in layer-5 pyramidal cells (L5-PCs) of the ACC strongly, reproducibly, and selectively decreased challenge-induced impulsivity. Differential gene expression analysis across murine ACC cell-types and 402 GPCRs revealed that - among G i -coupled receptor-encoding genes - Grm2 is the most selectively expressed in L5-PCs while alternative targets were scarce. Validating our approach, we confirmed that mGluR2 activation reduced premature responding. These results suggest G i -coupled receptors in ACC L5-PCs as therapeutic targets for impulse control disorders.

Background: The medial prefrontal cortex (PFC) is crucial for regulating craving and alcohol seeking in alcohol use disorder (AUD) patients and alcohol seeking in animal models. Maladaptive changes in volitional ethanol (EtOH) intake have been associated with PFC function, yet synaptic adaptations within PFC have not been consistently detected in voluntary drinking rodent models. At least 80% of the neurons in PFC are glutamatergic pyramidal cells. Pyramidal cells provide the predominant cortical output to several brain regions relevant to AUD, including structures within the telencephalon (IT: e.g., basal ganglia, amygdala, other neocortical regions) and outside the telencephalon (ET: e.g., lateral hypothalamus, midbrain monoaminergic structures, thalamus)., Methods: In addition to their anatomical distinctions, studies from several laboratories have revealed that prefrontal cortical IT and ET pyramidal cells may be differentiated by specific electrophysiological parameters. These distinguishable parameters make it possible to readily classify pyramidal cells into separable subtypes. Here, we employed and validated the hyperpolarization sag ratio as a diagnostic proxy for separating ET (type A) and IT (type B) neurons. We recorded from deep-layer prelimbic PFC pyramidal cells of mice 1 day after 4 to 5 weeks of intermittent access (IA) EtOH exposure., Results: Membrane properties were not altered by IA EtOH, but excitatory postsynaptic strength onto IT type B neurons was selectively enhanced in slices from IA EtOH mice. The increased excitatory drive was accompanied by enhanced mGlu 2/3 receptor plasticity on IT type B neurons, providing a potential translational approach to mitigate cognitive and motivational changes to PFC function related to binge drinking., Conclusions: Together, these studies provide insight into the specific PFC neurocircuits altered by voluntary drinking. In addition, the findings provide an additional rationale for developing compounds that potentiate mGlu 2 and/or mGlu 3 receptor function as potential treatments for AUD., (© 2021 by the Research Society on Alcoholism.)

Purpose: The three-dimensional configurations of rod and cone bipolar cell (BC) dendrites and horizontal cell (HC) processes outside rod and cone synaptic terminals have not been fully elucidated. We reveal how these neurites are mutually arranged to coordinate formation and maintenance of the postsynaptic complex of ribbon synapses in mouse and monkey retinas., Methods: Serial section transmission electron microscopy was utilized to reconstruct BC and HC neurites in macaque monkey and mouse, including metabotropic glutamate receptor 6 (mGluR6)-knockout mice., Results: Starting from sporadically distributed branching points, rod BC and HC neurites (B and H, respectively) took specific paths to rod spherules by gradually adjusting their mutual positions, which resulted in a closed alternating pattern of H‒B‒H‒B neurites at the rod spherule aperture. This order corresponded to the array of elements constituting the postsynaptic complex of ribbon synapses. We identified novel helical coils of HC processes surrounding the rod BC dendrite in both mouse and macaque retinas, and these structures occurred more frequently in mGluR6-knockout than wild-type mouse retinas. Horizontal cell processes also formed hook-like protrusions that encircled cone BC and HC neurites below the cone pedicles in the macaque retina., Conclusions: Bipolar and horizontal cell neurites take specific paths to adjust their mutual positions at the rod spherule aperture. Some HC processes are helically coiled around rod BC dendrites or form hook-like protrusions around cone BC dendrites and HC processes. Loss of mGluR6 signaling may be one factor promoting unbalanced neurite growth and compensatory neurite coiling.

The ability of humans and animals to localize the source of a sound in a complex acoustic environment facilitates communication and survival. Two cues are used for sound localization at horizontal planes, interaural time and level differences (ITD and ILD), which are analyzed by distinct neural circuits in the brainstem. Here, we review the studies on metabotropic glutamate receptor (mGluR)-mediated neuromodulation of both intrinsic and synaptic properties of brainstem neurons in these circuits. Both mammalian and avian animal models have been used, with each having their advantages that are not present in the other. For the mammalian model, we discuss mGluR neuromodulation in the ILD circuit, with an emphasis on the recent discovery of differential modulation of synaptic transmission of different transmitter release modes. For the avian model, we focus on reviewing mGluR neuromodulation in the ITD pathway, with an emphasis on tonotopic distribution and synaptic plasticity of mGluR modulation in coincidence detector neurons. Future works are proposed to further investigate the functions and mechanisms of mGluRs in the sound localization circuits., (Copyright © 2020 Goel, Peng and Lu.)

Antagonists of the group II metabotropic glutamate (mGlu) 2/3 receptors have been shown to have a rapid antidepressant effect. GABAergic interneurons play a crucial role in major depressive disorder (MDD) and possibly mediate the rapid antidepressant effect. However, how mGlu2/3 receptors regulate synaptic activities to GABAergic interneurons is not fully understood. In the present work, we studied the effect of mGlu2/3 receptors on excitatory and inhibitory synaptic activities to somatostatin (SST)- and parvalbumin (PV)-expressing interneurons, two major types of GABAergic interneurons, in the anterior cingulate cortex (ACC) that is strongly indicated in MDD. We found that activation of mGlu2/3 receptors by (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl) glycine (DCG-IV), an agonist of mGlu2/3 receptors, remarkably reduced the frequency, but not the amplitude, of spontaneous and miniature excitatory postsynaptic currents (sEPSCs and mEPSCs) and the amplitude of evoked EPSCs in both types. The reduction in the frequency of sEPSCs and the amplitude of evoked EPSCs was more pronounced in SST interneurons. DCG-IV, however, did not affect spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs) and evoked IPSCs in both types. LY341495, an antagonist of mGlu2/3 receptors, enhanced the amplitude of evoked EPSCs without affecting sEPSCs and mEPSCs in both types. It also did not affect sIPSCs and evoked IPSCs except slightly increasing the frequency of mIPSCs in SST interneurons. Our results indicate that mGlu2/3 receptors primarily regulate excitatory synaptic activities to the two types of GABAergic interneurons in the ACC., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The main symptoms of Alzheimer's disease (AD) is the loss of learning and memory ability, of which biological basis is synaptic plasticity. Aluminium has been found to cause changes in synaptic plasticity, but its molecular mechanism was unclear. In this study, Sprague-Dawley rats were injected with aluminium maltol (Al(mal) 3 ) through the lateral ventricle to establish an AD-like model. Y-maze, electrophysiological measurements, Golgi staining, scanning electron microscopy, quantitative real-time polymerase chain reaction, and western blot techniques were used to investigate regulation of the metabolic glutamate receptor 1 (mGluR1) in synaptic plasticity impairment induced by Al(mal) 3 . The results showed that Al(mal) 3 inhibited the induction and maintenance of long-term potentiation in the hippocampal CA1 region. During this process, the expression of mGluR1 was up-regulated and it inhibited the expression and phosphorylation of the N-methyl-D-aspartic acid receptors (NMDARs). This mainly affected NMDAR1 and NMDAR2B but did not affect protein kinase C expression., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

Transient receptor potential canonical (TRPC) proteins constitute a group of receptor-operated calcium-permeable nonselective cationic membrane channels of the TRP superfamily. They are largely expressed in the hippocampus and are able to modulate neuronal functions. Accordingly, they have been involved in different hippocampal functions such as learning processes and different types of memories, as well as hippocampal dysfunctions such as seizures. This review covers the mechanisms of activation of these channels, how these channels can modulate neuronal excitability, in particular the after-burst hyperpolarization, and in the persistent activity, how they control synaptic plasticity including pre- and postsynaptic processes and how they can interfere with cell survival and neurogenesis., Competing Interests: The authors declare no competing financial interests. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

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.

In recent years, the survey of metabolic glutamate receptor 4 (GRM4) in tumor biology has been gradually concerned. There are currently few studies on GRM4 in osteosarcoma, and the biological function is not clear. Analysis of TCGA database showed that there was no substantial deviation in the expression of GRM4 between osteosarcoma and normal tissues. In the subsequent experiments, there is no significant difference in either mRNA or protein levels among immortalized human osteoblasts and various osteosarcoma cells. With the overexpression of GRM4, cell proliferation, migration and invasion were inhibited obviously. It was further revealed that GRM4 can interact with CBX4 to restrict the nuclear localization of CBX4 and affect the transcriptional activity of HIF-1α. This is the evidence supporting the interaction between GRM4 and CBX4, which could inhibit the malignant behavior of osteosarcoma cells through the GRM4/CBX4/HIF-1α signaling pathway.

Rationale: Because chronic cocaine exposure produces profound effects on brain glutamate function, this system has been investigated as a target for novel medications for cocaine use disorder. Studies in animal models have provided encouraging results for drugs that target metabotropic glutamate receptors (mGluR), particularly group II mGluRs which includes mGluR2 and mGluR3 receptors., Objective: The present study examined the effects of the mGluR2/3 receptor-selective agonist, (-)-2-oxa-4-aminobicylco hexane-4,6-dicarboxylic acid (LY379268), in male rhesus monkeys self-administering cocaine under two procedures that assess the strength of cocaine as a reinforcer., Methods and Results: In four monkeys, acute effects of LY379268 on food and cocaine self-administration were characterized using a multiple 10-response fixed-ratio food, progressive-ratio cocaine schedule of reinforcement. Maximum injections were delivered when the available cocaine dose was 0.01-0.1 mg/kg. When monkeys self-administered 0.03 mg/kg per injection cocaine, LY379268 (0.001-0.56 mg/kg, i.v.), increased cocaine injections and disrupted food-maintained responding. Another group of monkeys (n = 3) responded under a food-cocaine choice procedure in which a dose-effect curve for self-administered cocaine (0.0, 0.003-0.1 mg/kg per injection) was generated daily. Acute LY379268 (0.01-0.1 mg.kg, i.v.) produced a shift in allocation of responding towards cocaine without affecting the total reinforcers delivered. When treatment was extended to 5 consecutive days, tolerance developed to LY379268-induced increases in cocaine choice., Conclusions: These data from two complimentary nonhuman primate models of cocaine use disorder are consistently negative with respect to the potential of LY379268 as a pharmacotherapy for reducing ongoing cocaine use.

Developing central synapses exhibit robust plasticity and undergo experience-dependent remodeling. Evidently, synapses in sensory systems such as auditory brainstem circuits mature rapidly to achieve high-fidelity neurotransmission for sound localization. This depends on a developmental switch in AMPAR composition from slow-gating GluA1-dominant to fast-gating GluA4-dominant, but the mechanisms underlying this switch remain unknown. We hypothesize that patterned stimuli mimicking spontaneous/sound evoked activity in the early postnatal stage drives this gating switch. We examined activity-dependent changes in evoked and miniature excitatory postsynaptic currents (eEPSCs and mEPSCs) at the calyx of Held synapse by breaking through the postsynaptic membrane at different time points following 2 min of theta burst stimulation (TBS) to afferents in mouse brainstem slices. We found the decay time course of eEPSCs accelerated, but this change was not apparent until > 30 min after TBS. Histogram analyses of the decay time constants of mEPSCs for naive and tetanized synapses revealed two populations centered around τ fast  ≈ 0.4 and 0.8 ms, but the relative weight of the τ 0.4 population over the τ 0.8 population increased significantly only in tetanized synapses. Such changes are blocked by NMDAR or mGluR1/5 antagonists or inhibitors of CaMKII, PKC and protein synthesis, and more importantly precluded in GluA4 -/- synapses, suggesting GluA4 is the substrate underlying the acceleration. Our results demonstrate a novel form of plasticity working through NMDAR and mGluR activation to trigger a gating switch of AMPARs with a temporally delayed onset of expression, ultimately enhancing the development of high-fidelity synaptic transmission.

It is a common opinion that metabotropic glutamate receptor subtype 6 (mGluR6) is expressed exclusively in the retina, and in particular in the dendrites of ON-bipolar cells. Glutamate released in darkness from photoreceptors activates mGluR6, which is negatively associated with a membrane non-selective cation channel, the transient receptor potential melanoma-related 1, TRPM1, resulting in cell hyperpolarization. The evidence that mGluR6 is expressed not only in the retina but also in other tissues and cell populations has accumulated over time. The expression of mGluR6 has been identified in microglia, bone marrow stromal and prostate cancer cells, B lymphocytes, melanocytes and keratinocytes and non-neural tissues such as testis, kidney, cornea, conjunctiva, and eyelid. The receptor also appears to be expressed in brain areas, such as the hypothalamus, cortex, hippocampus, nucleus of tractus solitarius, superior colliculus, axons of the corpus callosum and accessory olfactory bulb. The pharmacological activation of mGluR6 in the hippocampus produced an anxiolytic-like effect and in the periaqueductal gray analgesic potential. This review aims to collect all the evidence on the expression and functioning of mGluR6 outside the retina that has been accumulated over the years for a broader view of the potential of the receptor whose retinal confinement appears understimated., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Metabotropic glutamate (mGlu) receptors represent the largest family of glutamate receptors in mammals and act as fine tuners of the chemical transmission in central nervous system (CNS). In the last decade, results concerning the expression and the subcellular localization of mGlu receptors further clarified their role in physio-pathological conditions. Concomitantly, their pharmacological characterization largely improved thanks to the identification of new compounds (chemical ligands and antibodies recognizing epitopic sequences of the receptor proteins) that allowed to decipher the protein compositions of the naive receptors. mGlu receptors are expressed at the presynaptic site of chemical synapses. Here, they modulate intraterminal enzymatic pathways controlling the migration and the fusion of vesicles to synaptic membranes as well as the phosphorylation of colocalized receptors. Both the control of transmitter exocytosis and the phosphorylation of colocalized receptors elicited by mGlu receptors are relevant events that dictate the plasticity of nerve terminals, and account for the main role of presynaptic mGlu receptors as modulators of neuronal signalling. The role of the presynaptic mGlu receptors in the CNS has been the matter of several studies and this review aims at briefly summarizing the recent observations obtained with isolated nerve endings (we refer to as synaptosomes). We focus on the pharmacological characterization of these receptors and on their receptor-receptor interaction / oligo-dimerization in nerve endings that could be relevant to the development of new therapeutic approaches for the cure of central pathologies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the presence of neuritic plaques and neurofibrillary tangles. The impaired synaptic plasticity and dendritic loss at the synaptic level is an early event associated with the AD pathogenesis. The abnormal accumulation of soluble oligomeric amyloid-β (Aβ), the major toxic component in amyloid plaques, is viewed to trigger synaptic dysfunctions through binding to several presynaptic and postsynaptic partners and thus to disrupt synaptic transmission. Over time, the abnormalities in neural transmission will result in cognitive deficits, which are commonly manifested as memory loss in AD patients. Synaptic plasticity is regulated through glutamate transmission, which is mediated by various glutamate receptors. Here we review recent progresses in the study of metabotropic glutamate receptors (mGluRs) in AD cognition. We will discuss the role of mGluRs in synaptic plasticity and their modulation as a possible strategy for AD cognitive improvement.

Previous studies have demonstrated that antagonists of mGluR1, but not mGluR5, are neuroprotective in models of cerebral ischemia. To investigate the individual roles of mGlu1 and mGlu5 receptors in in vitro model of cerebral ischemia we used low doses of the non-selective group I agonist DHPG and mGlu1 and mGlu5 selective positive allosteric modulators (PAMs). In hippocampal slices subjected to 30 min oxygen-glucose deprivation (OGD), DHPG (1 μM) and the mGluR5 PAM (VU0092273) significantly reduced OGD-induced CA1 injury monitored by propidium iodide staining of the slices and quantitative analysis of CA1 neurons. In contrast, the mGluR1 PAM (VU0483605) showed no neuroprotection. These protective effects of DHPG and VU0092273 were prevented by inhibition of PI3K/Akt pathway by LY294002. The mGluR5 PAM (VU0092273) also prevented GluA2 down-regulation triggered by ischemic injury, via PI3K/Akt pathway, revealing a further contribution to its neuroprotective effects by reducing the excitotoxic effects of increased Ca 2+ influx through GluA2-lacking AMPA receptors. Furthermore, immunohistochemical assays confirmed the neuroprotective effect of VU0092273 and revealed activation of glia, indicating the involvement reactive astrogliosis in the mechanisms of neuroprotection. Our data suggest that selective activation/potentiation of mGluR5 signalling represents a promising strategy for the development of new interventions to reduce or prevent ischemia-induced neuronal death., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The dorsal striatum, apart from controlling voluntary movement, displays a recently demonstrated pain inhibition. It is connected to the descending pain modulatory system and in particular to the rostral ventromedial medulla through the medullary dorsal reticular nucleus. Diseases of the basal ganglia, such as Parkinson's disease, in addition to being characterized by motor disorders, are associated with pain and hyperactivation of the excitatory transmission. A way to counteract glutamatergic hyperactivation is through the activation of group III metabotropic glutamate receptors (mGluRs), which are located on presynaptic terminals inhibiting neurotransmitter release. So far the mGluRs of group III have been the least investigated, owing to a lack of selective tools. More recently, selective ligands for each mGluR of group III, in particular positive and negative allosteric modulators, have been developed and the role of each subtype is starting to emerge. The neuroprotective potential of group III mGluRs in pathological conditions, such as those characterized by elevate glutamate, has been recently shown. In the dorsal striatum, mGluR7 and mGluR8 are located at glutamatergic corticostriatal terminals and their stimulation inhibits pain in pathological conditions such as neuropathic pain. The two receptors in the dorsal striatum have instead a different role in pain control in normal conditions. This review will discuss recent results focusing on the contribution of mGluR7 and mGluR8 in the dorsal striatal control of pain. The role of mGluR4, whose antiparkinsonian activity is widely reported, will also be addressed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The serotonin 5-HT 2A and glutamate mGlu 2 receptors continue to attract particular attention, given their implication in psychosis associated with schizophrenia and the mechanism of action of atypical antipsychotics and a new class of antipsychotics, respectively. A large body of evidence indicates a functional crosstalk between both receptors in the brain, but the underlying mechanisms are not entirely elucidated. Here, we have explored the influence of 5-HT 2A receptor upon the phosphorylation pattern of mGlu 2 receptor in light of the importance of specific phosphorylation events in regulating G protein-coupled receptor signaling and physiological outcomes. Among the five mGlu 2 receptor-phosphorylated residues identified in HEK-293 cells, the phosphorylation of Ser 843 was enhanced upon mGlu 2 receptor stimulation by the orthosteric agonist LY379268 only in cells co-expressing the 5-HT 2A receptor. Likewise, administration of LY379268 increased mGlu 2 receptor phosphorylation at Ser 843 in prefrontal cortex of wild-type mice but not 5-HT 2A -/- mice. Exposure of HEK-293 cells co-expressing mGlu 2 and 5-HT 2A receptors to 5-HT also increased Ser 843 phosphorylation state to a magnitude similar to that measured in LY379268-treated cells. In both HEK-293 cells and prefrontal cortex, Ser 843 phosphorylation elicited by 5-HT 2A receptor stimulation was prevented by the mGlu 2 receptor antagonist LY341495, while the LY379268-induced effect was abolished by the 5-HT 2A receptor antagonist M100907. Mutation of Ser 843 into alanine strongly reduced G i/o signaling elicited by mGlu 2 or 5-HT 2A receptor stimulation in cells co-expressing both receptors. Collectively, these findings identify mGlu 2 receptor phosphorylation at Ser 843 as a key molecular event that underlies the functional crosstalk between both receptors.

Taste changes caused by the use of platinum drugs have been described. However, few studies qualify the impaired tastes and whether these changes are derived exclusively from chemotherapy (QTx)., Aims: Evaluation of changes in sweet, sour, salty, bitter, and umami tastes in patients receiving QTx with platinum drugs was the aim of this study., Methods: A total of 43 subjects, 21 from the study group and 22 from the control, were studied in two time periods, one before the start of QTx (T0) and another after two cycles of QTx (T1). The usual dietary intake, body mass index (BMI), handgrip strength and fatigue (through the fatigue pictogram) were evaluated to characterize the group studied. Taste Strips tests were performed for all 4 tastes and umami was studied by comparing Likert's scale using monosodium glutamate (GMS) food. Statistical analysis was performed using repeated measures (ANOVA), mixed model, with significance level p≤0.05., Results: Salty and sour were the most affected tastes in the study group (p = 0.001 and 0.05); as well as the ionotropic receptors (p = 0.02) responsible for identifying these tastes. There was a difference between the times for BMI, dynamometry and impact in daily activities, by the fatigue pictogram (p = 0.008, 0.009 and 0.006 respectively)., Conclusion: These findings suggest an important role in altering taste recognition, mainly in salty and sour tastes, identified by ionotropic receptors, which seems to be related to dietary changes. QTx has demonstrated a contribution to impairment of functionality and fatigue., (Copyright © 2019. Published by Elsevier Inc.)

Lysophosphatidic acid (LPA) is a glycerophospholipid that can be detected in serum, saliva and cerebrospinal fluid. However, the effect of LPA on neuronal death and survival has not been fully determined. In the present study, we investigated the potential neurotoxic effect of LPA in primary cultured cortical neurons. Treatment with LPA (0.5, 1 and 5 μM) markedly decreased neuronal viability, increased lactate dehydrogenase (LDH) release and promoted apoptosis in cortical neurons. The results of western blot showed that LPA increased the expression of endoplasmic reticulum (ER) stress associated factors, and the protein misfolding inhibitor 4-phenylbutyric acid (4-PBA) attenuated LPA-induced toxicity. In addition, treatment with LPA did not alter the expression and distribution of Homer1 in cortical neurons. The protein levels of metabotropic glutamate receptor 1 (mGluR1), but not metabotropic glutamate receptor 5 (mGluR5), were significantly increased by LPA at 12 and 24 h after treatment. Knockdown of Homer1 using specific siRNA partially prevented the LPA-induced neurotoxicity and ER stress. Furthermore, the results of Ca 2+ imaging showed that treatment with LPA induced intracellular Ca 2+ release, which could be partially prevented by 4-PBA and downregulation of Homer1. The LPA-induced intracellular Ca 2+ release was associated with ER Ca 2+ release through the Homer1-mGluR1 pathway. In summary, our results showed that LPA treatment induced ER stress and apoptosis in cortical neurons, and its neurotoxicity was partially mediated by Ca 2+ release from the ER via the Homer1/mGluR1 pathway., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

In search of the molecular identities of cold-sensing receptors, we carried out an unbiased genetic screen for cold-sensing mutants in C. elegans and isolated a mutant allele of glr-3 gene that encodes a kainate-type glutamate receptor. While glutamate receptors are best known to transmit chemical synaptic signals in the CNS, we show that GLR-3 senses cold in the peripheral sensory neuron ASER to trigger cold-avoidance behavior. GLR-3 transmits cold signals via G protein signaling independently of its glutamate-gated channel function, suggesting GLR-3 as a metabotropic cold receptor. The vertebrate GLR-3 homolog GluK2 from zebrafish, mouse, and human can all function as a cold receptor in heterologous systems. Mouse DRG sensory neurons express GluK2, and GluK2 knockdown in these neurons suppresses their sensitivity to cold but not cool temperatures. Our study identifies an evolutionarily conserved cold receptor, revealing that a central chemical receptor unexpectedly functions as a thermal receptor in the periphery., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Declines in sleep amount and quality-characterized by excessive daytime sleepiness and an inability to sleep at night-are common features of aging. Sleep dysfunction is also associated with age-related ailments and diseases, suggesting that sleep is functionally relevant to the aging process. Metabotropic glutamate receptors (mGluRs)-which are critical regulators of neurotransmission and synaptic plasticity-have been implicated in both age-related disease and sleep regulation. Therefore, in this study, we examined the sleep and aging effect of complete genetic loss of mGluR signaling in Drosophila melanogaster. Genetic knockdown of the sole Drosophila mGluR-known as DmGluRA-reduced daytime wakefulness and nighttime sleep, recapitulating age-related sleep changes that occur across species. Furthermore, loss of DmGluRA significantly reduced lifespan and exacerbated age-related sleep loss in older flies. Thus, we identify DmGluRA as a novel regulator of sleep whose loss results in an age-relevant sleep phenotype that is associated with shortened lifespan. This is the first evidence that mGluR signaling regulates sleep/wake in a manner that is relevant to the aging process., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Measurement of cytosolic calcium activity in single neuron and quantification of response to drug treatment over a longer period remain challenging. Especially, analysis of amplitude, frequency, and delay in calcium response in G-protein coupled receptors (GPCR) targeting drug-treated neurons is complicated due to inherent heterogeneity. To address this, we have utilized k- means clustering to identify various sub-populations. Here we focus on measuring drug dose response in the single neuron by means of high-resolution confocal imaging. Metabotropic glutamate receptor was activated using 3,5-dihydroxyphenylglycine (DHPG). The result reveals an unusual delay in calcium response for higher dose particularly in responding neurons. The proposed methodology can be used for selection of drug dose and optimization of the time window for neurodegenerative diseases.

Stress can precipitate or worsen symptoms of many psychiatric disorders by dysregulating glutamatergic function within the prefrontal cortex (PFC). Previous studies suggest that antagonists of group II metabotropic glutamate (mGlu) receptors (mGlu 2 and mGlu 3 ) reduce stress-induced anhedonia through actions in the PFC, but the mechanisms by which these receptors act are not known. We now report that activation of mGlu 3 induces long-term depression (LTD) of excitatory transmission in the PFC at inputs from the basolateral amygdala. Our data suggest mGlu 3 -LTD is mediated by postsynaptic AMPAR internalization in PFC pyramidal cells, and we observed a profound impairment in mGlu 3 -LTD following a single, 20-min restraint stress exposure. Finally, blocking mGlu 3 activation in vivo prevented the stress-induced maladaptive changes to amydalo-cortical physiology and motivated behavior. These data demonstrate that mGlu 3 mediates stress-induced physiological and behavioral impairments and further support the potential for mGlu 3 modulation as a treatment for stress-related psychiatric disorders.

Here, we investigated the effects and molecular mechanisms of metabotropic glutamate receptor 6 (mGluR6) on rat embryonic neural stem cells (NSCs). Overexpression of mGluR6 significantly promoted the proliferation of NSCs and increased the diameter of neutrospheres after treatment for 24 h, 48 h and 72 h. Overexpression of mGluR6 promoted G1 to S phase transition, with significantly decreased cell ratio in G1/G0 phase but significantly increased cell ratio in S phase. Additionally, mGluR6 overexpression for 48 h decreased the early and late apoptosis significantly. Moreover, overexpression of mGluR6 significantly increased the expression of p-ERK1/2, Cyclin D1 and CDK2, while the expression of p-p38 was significantly decreased. On the contrary, these effects of mGluR6 overexpression were reversed by mGluR6 knockdown. In conclusion, mGluR6 promotes the proliferation of NSCs by activation of ERK1/2-Cyclin D1/CDK2 signaling pathway and inhibits the apoptosis of NSCs by blockage of the p38 MAPK signaling pathway.

Rodents extract information about nearby objects from the movement of their whiskers through dynamic computations that are carried out by a network of forebrain structures that includes the thalamus and the primary sensory (S1BF) and motor (M1wk) whisker cortices. The posterior nucleus (Po), a higher order thalamic nucleus, is a key hub of this network, receiving cortical and brainstem sensory inputs and innervating both motor and sensory whisker-related cortical areas. In a recent study in rats, we showed that Po inputs differently impact sensory processing in S1BF and M1wk. Here, in C57BL/6 mice, we measured Po synaptic bouton layer distribution and size, compared cortical unit response latencies to "in vivo" Po activation, and pharmacologically examined the glutamatergic receptor mechanisms involved. We found that, in S1BF, a large majority (56%) of Po axon varicosities are located in layer (L)5a and only 12% in L2-L4, whereas in M1wk this proportion is inverted to 18% and 55%, respectively. Light and electron microscopic measurements showed that Po synaptic boutons in M1wk layers 3-4 are significantly larger (~ 50%) than those in S1BF L5a. Electrical Po stimulation elicits different area-specific response patterns. In S1BF, responses show weak or no facilitation, and involve both ionotropic and metabotropic glutamate receptors, whereas in M1wk, unit responses exhibit facilitation to repetitive stimulation and involve ionotropic NMDA glutamate receptors. Because of the different laminar distribution of axon terminals, synaptic bouton size and receptor mechanisms, the impact of Po signals on M1wk and S1BF, although simultaneous, is likely to be markedly different.

Neurons in various sensory systems show some level of spontaneous firing in the absence of sensory stimuli. In the auditory system spontaneous firing has been shown at all levels of the auditory pathway from spiral ganglion neurons in the cochlea to neurons of the auditory cortex. This internal "noise" is normal for the system and it does not interfere with our ability to perceive silence or analyze sound. However, this internal noise can be elevated under pathological conditions, leading to the perception of a phantom sound known as tinnitus. The efforts of many research groups, including our own, led to the development of a mechanistic understanding of this process: After cochlear insult the input to the central auditory system becomes markedly reduced. As a result, the neural activity in the central auditory system is enhanced to compensate for this reduced input. Such hyperactivity is hypothesized to be interpreted by the brain as a presence of sound. This implies that suppression of hyperactivity should reduce/eliminate tinnitus. This review explores research from our laboratory devoted to identifying the mechanism underlying residual inhibition of tinnitus, a brief suppression of tinnitus following a sound stimulus. The key mechanisms that govern neural suppression of spontaneous activity in animals closely resemble clinical psychoacoustic findings of residual inhibition (RI) observed in tinnitus patients. This suppression is mediated by metabotropic glutamate receptors (mGluRs). Lastly, drugs targeting mGluRs suppress spontaneous activity in auditory neurons and reduce/eliminate behavioral signs of tinnitus in mice. Thus, these drugs are therapeutically relevant for tinnitus suppression in humans., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

This study is to investigate the effect of metabotropic glutamate receptor 7 (mGluR7) on the proliferation of human embryonic neural stem cells (NSCs) and its molecular mechanism.Human embryonic NSCs were isolated. The pCMV2-GV146-GFP-mGluR7 plasmid was transfected to over-express mGluR7 while mGluR7 siRNA was transfected to knockdown mGluR7. MTT assay was used to analyze cell proliferation. Flow cytometry was used to detect cell cycle and apoptosis. Protein and mRNA levels were analyzed by Western blot and RT-qPCR, respectively.The viability of human NSCs and the diameter of neurospheres after 24 hours, 48 hours, and 72 hours of transfection significantly increased by mGluR7 overexpression whereas significantly decreased by mGluR7 knockdown. Ki-67 expression was up-regulated by mGluR7 overexpression whereas down-regulated by mGluR7 siRNA, indicating a promotive effect of mGluR7 on NSC proliferation. After mGluR7 overexpression, G1/G0 phase cell ratio dropped significantly compared with control group, while the S phase cell ratio increased. mGluR7 silencing arrested human NSCs at G1/G0 phase. After 48 hours of transfection, there was a decrease of apoptosis by mGluR7 overexpression, while mGluR7 silencing induced apoptosis of human NSCs. Additionally, overexpression of mGluR7 up-regulated the expression of p-serine/threonine kinase (AKT), cyclin D1, and cyclin-dependent kinase 2 (CDK2). The mGluR7 knockdown had opposite effects. Similarly, mGluR7 down-regulated the expression of Caspase-3/9, while the mGluR7 knockdown promoted this.mGluR7 can promote the proliferation of human embryonic cortical NSCs in vitro. This effect may be mediated by promoting cell cycle progression, inhibiting cell apoptosis, activating the AKT signaling pathway, and inhibiting the Caspase-3/9 signaling pathway.

Methamphetamine (METH) increases metabolic neuronal activity in the mesolimbic dopamine (DA) system and mediates the reinforcing effect. To explore the underlying mechanism of acupuncture intervention in reducing METH-induced behaviors, we investigated the effect of acupuncture on locomotor activity, ultrasonic vocalizations, extracellular DA release in the nucleus accumbens (NAcs) using fast-scan cyclic voltammetry and alterations of brain temperature (an indicator of local brain metabolic activity) produced by METH administration. When acupuncture was applied to HT7, but not TE4, both locomotor activity and 50-kHz ultrasonic vocalizations were suppressed in METH-treated rats. Acupuncture at HT7 attenuated the enhancement of electrically stimulated DA release in the NAc of METH-treated rats. Systemic injection of METH produced a sustained increase in NAc temperature, which was reversed by the DA D1 receptor antagonist SCH 23390 or acupuncture at HT7. Acupuncture inhibition of METH-induced NAc temperature was prevented by pre-treatment with a group II metabotropic glutamate receptors (mGluR2/3) antagonist EGLU into the NAc or mimicked by injection of an mGluR2/3 agonist DCG-IV into the NAc. These results suggest that acupuncture reduces extracellular DA release and metabolic neuronal activity in the NAc through activation of mGluR2/3 and suppresses METH-induced affective states and locomotor behavior., (© 2018 Society for the Study of Addiction.)

Peripheral group III metabotropic glutamate receptors (mGluRs) function to modulate pain signaling in inflammatory states. Here, we established in vivo experimental settings, including dynamic weight bearing test and in vivo single nerve recording, to elucidate how the group III mGluRs contribute to inhibiting pain transmission at the peripheral sensory nerve terminal in inflammatory states (1 and 3 days) elicited by Complete Freund's Adjuvant (CFA). As a result, CFA-induced nociceptive behaviors were significantly alleviated after administration of 100 and 200 μM L-AP4 (l-2-amino-4-phosphonobutylate; group III mGluR agonist). In addition, neuronal discharges evoked by 6- and 26-g von Frey filaments at the nerve significantly decreased after administration of 200 μM L-AP4. However, this event was not observed in non-inflammatory state. These results suggest that the group III mGluRs negatively regulate nociceptive behavior and pain transmission by lessening neuronal firing rates at the peripheral nerve in inflammation., (Copyright © 2018. Published by Elsevier B.V.)

Increasing evidence has indicated that metabotropic glutamate receptor‑7 (mGluR7) is an important target for reducing anxiety and stress‑associated behaviours. Notably, mood disorders exhibit high levels of comorbidity with gastrointestinal dysfunction; however, the role of mGluR7 outside of the central nervous system is currently unknown. Activating mGluR7 likely increases colonic secretory function. Therefore, the present study aimed to evaluate the possible effects of mGluR7 on the visceral hypersensitivity of irritable bowel syndrome (IBS) in rats. The expression levels of mGluR7 were assessed in the colon tissues of rats with neonatal maternal separation (NMS)‑induced visceral hypersensitivity using reverse transcription‑quantitative polymerase chain reaction, western blotting and immunohistochemistry. In addition, the mGluR7 agonist AMN082 (3 or 10 mg/kg; i.p.) was administered 1 h prior to the visceral hypersensitivity test, and the effects of AMN082 were then observed on the nuclear factor (NF)‑κB signalling pathway. The mRNA and protein expression levels of mGluR7 were upregulated in the colon mucosa of NMS rats compared with in normal control rats. Notably, administration of AMN082 (10 mg/kg) attenuated colorectal distension (CRD)‑induced visceral hypersensitivity in NMS rats. In addition, interleukin‑10 and transforming growth factor‑β mRNA expression levels were upregulated, whereas interferon‑γ mRNA expression levels were downregulated in the NMS + AMN082 group compared with in NMS rats. The number of cluster of differentiation 3+ T cells in the intestinal mucosa and myeloperoxidase activity were decreased in NMS + AMN082 rats. Furthermore, AMN082 treatment reduced the protein expression levels of phosphorylated‑NF‑κB in the colon tissue of NMS rats. These results indicated that activation of mGluR7 may attenuate CRD‑induced visceral hypersensitivity in experimental IBS and reduce the abnormal immune cytokine response. In addition, it was suggested that the role of AMN082 in modulating the inflammatory response may be partially associated with inhibiting NF‑κB activation. These data suggested that targeting mGluR7 may be useful in the treatment of stress‑associated IBS.

The peptide transmitter N-acetylaspartylglutamate (NAAG) and its receptor, the type 3 metabotropic glutamate receptor (mGluR3, GRM3), are prevalent and widely distributed in the mammalian nervous system. Drugs that inhibit the inactivation of synaptically released NAAG have procognitive activity in object recognition and other behavioral models. These inhibitors also reverse cognitive deficits in animal models of clinical disorders. Antagonists of mGluR3 block these actions and mice that are null mutant for this receptor are insensitive to the actions of these procognitive drugs. A positive allosteric modulator of this receptor also has procognitive activity. While some data suggest that drugs acting on mGluR3 achieve their procognitive action by increasing arousal during acquisition training, exploration of the procognitive efficacy of NAAG is in its early stages and thus substantial opportunities exist to define the breadth and nature of this activity., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Drugs of abuse modify synaptic long-term potentiation and long-term depression (LTD) in the nucleus accumbens, and the impairment of synaptic plasticity in this brain region may be a universal feature of drug addiction. It is unknown whether metabotropic glutamate receptors (mGluRs) play a role in synaptic plasticity induced by drugs such as morphine. The neurochemical, electrophysiological, and Western blotting experiments reported here reveal a novel form of LTD in synapses of the shell region of the nucleus accumbens induced in vivo by low-frequency stimulation of the medial prefrontal cortex. This plasticity required the activation of N-methyl-d-aspartate receptors and mGluR2/3 but not mGluR5. The expression of mGluR2/3 was downregulated during withdrawal from repeated morphine exposure (10 days after the last injection), resulting in impaired low-frequency stimulation-induced LTD. These results indicate that withdrawal-induced mGluR2/3 downregulation alters neural plasticity after morphine exposure, which may be a mechanism contributing to drug addiction., (Copyright © 2018 Elsevier B.V. All rights reserved.)

A recently reported rapid potentiation of NMDA receptors by Group I metabotropic glutamate receptors (mGluRIs) via a Homer protein link is distinct from the classical, relatively slow inhibitory G-protein-associated signaling triggered by mGluRI activation. The relationship between these two mechanisms remains unknown. Here, we focused on the mGluRI-dependent modulation of NMDAR response in hippocampal dentate gyrus granule cells and cerebellar granule cells of C57BL6-J mice and found that these two contrasting mechanisms overlap competitively on the time scale from hundreds of milliseconds to seconds, with the net effect depending on the cell type. At a shorter time interval (units of millisecond), the Homer-mediated signal from mGluRIs prevails, causing upregulation of NMDAR function, in both dentate gyrus granule cells and cerebellar granule cells. Our results shed light on the possible mechanisms of anti-schizophrenia drugs that disrupt Homer-containing protein link. SIGNIFICANCE STATEMENT Here we study modulation of NMDA receptors triggered by activation of metabotropic glutamate receptors Group I via two distinct pathways: classical G-protein signaling system and newly discovered high-speed modulatory mechanism associated with Homer-protein-containing direct molecular link. We found that these two contrasting mechanisms overlap competitively on the time scale from hundreds of milliseconds to seconds, with the net effect depending on the cell type. We have also found that both crosstalk mechanisms cause significant changes in synaptic strength and plasticity. Our results resolve an apparent discrepancy between earlier studies that demonstrated contradictive effects of Homer-containing protein link disruption on NMDA receptor signaling. On top of that, our data provide a plausible explanation for unclear action mechanisms of anti-schizophrenia drugs., (Copyright © 2018 O'Neill et al.)

Background: Serotonin 5-HT 2A and metabotropic glutamate 2 (mGlu2) are neurotransmitter G protein-coupled receptors (GPCRs) involved in the signaling mechanisms underlying psychosis and schizophrenia treatment. Previous findings in mGlu2 knockout (KO) mice suggested that mGlu2 is necessary for head-twitch behavior, a rodent phenotype characteristic of hallucinogenic 5-HT 2A receptor agonists. However, the role of mGlu2 in the behavioral effects induced by antipsychotic drugs remains poorly understood. Here, we tested antipsychotic-like behavioral phenotypes induced by the atypical antipsychotic clozapine in mGlu2-KO mice and wild-type control littermates., Methods: Locomotor activity was tested in mGlu2-KO mice and control littermates injected (i.p.) with clozapine (1.5 mg/kg) or vehicle followed by MK801 (0.5 mg/kg), PCP (7.5 mg/kg), amphetamine (6 mg/kg), scopolamine (2 mg/kg), or vehicle. Using a virally (HSV) mediated transgene expression approach, the role of frontal cortex mGlu2 in the modulation of MK801-induced locomotor activity by clozapine treatment was also evaluated., Results: The effect of clozapine on hyperlocomotor activity induced by the dissociative drugs MK801 and phencyclidine (PCP) was decreased in mGlu2-KO mice as compared to controls. Clozapine treatment, however, reduced hyperlocomotor activity induced by the stimulant drug amphetamine and the deliriant drug scopolamine in both wild-type and mGlu2-KO mice. Virally mediated over-expression of mGlu2 in the frontal cortex of mGlu2-KO mice rescued the ability of clozapine to reduce MK801-induced hyperlocomotion., Conclusion: These findings further support the existence of a functionally relevant crosstalk between 5-HT 2A and mGlu2 receptors in different preclinical models of antipsychotic activity.

Cocaine exposure induces plasticity of glutamatergic synapses of medium spiny neurons (MSNs) in the nucleus accumbens (NAc), which has been proposed to contribute to its addictive behavior. The mechanisms underlying cocaine-induced plasticity are not fully understood. The orphan glutamate delta-1 (GluD1) receptor is a member of the ionotropic glutamate receptor family but does not function as a typical ligand-gated ion channel. Instead it serves a synaptogenic function by interacting with presynaptic Neurexin protein. Recent neuroanatomical studies have demonstrated enriched expression of GluD1 in the NAc but its role in reward behavior, MSN function, and drug-induced plasticity remains unknown. Using a combination of constitutive and conditional GluD1 KO models, we evaluated the effect of GluD1 ablation on cocaine-conditioned place preference (CPP) and cocaine-induced structural and functional plasticity. GluD1 KO mice showed higher cocaine CPP. Selective ablation of GluD1 from striatal neurons but not cortico-limbic excitatory neurons reproduced higher CPP. Higher cocaine preference in GluD1 KO correlated with an increase in spine density, greater maturation of dendritic spines, and basally upregulated spine-regulating active cofilin. GluD1 loss did not affect basal excitatory neurotransmission or plasticity but masked the generation of cocaine-induced silent synapses. Finally, loss of GluD1 increased the GluN2B subunit contribution to NMDA receptor currents in MSNs and a partial agonist of GluN2B-containing NMDA receptors normalized the higher active cofilin and cocaine preference in GluD1 KO mice. Together, these findings demonstrate a critical role of GluD1 in controlling susceptibility to cocaine preference and cocaine-induced plasticity by modulating NMDA receptor subunit contribution.

Dopamine neurons have different synaptic actions in the ventral and dorsal striatum (dStr), but whether this heterogeneity extends to dStr subregions has not been addressed. We have found that optogenetic activation of dStr dopamine neuron terminals in mouse brain slices pauses the firing of cholinergic interneurons in both the medial and lateral subregions, while in the lateral subregion the pause is shorter due to a subsequent excitation. This excitation is mediated mainly by metabotropic glutamate receptor 1 (mGluR1) and partially by dopamine D1-like receptors coupled to transient receptor potential channel 3 and 7. DA neurons do not signal to spiny projection neurons in the medial dStr, while they elicit ionotropic glutamate responses in the lateral dStr. The DA neurons mediating these excitatory signals are in the substantia nigra (SN). Thus, SN dopamine neurons engage different receptors in different postsynaptic neurons in different dStr subregions to convey strikingly different signals., Editorial Note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter)., Competing Interests: NC, SM, LY, AK, TM, SZ, AS, ST, JP, MA, RA, UK, SR No competing interests declared, (© 2018, Chuhma et al.)