Search Results (203)

mGlu5 metabotropic glutamate receptors are highly expressed and functional in early postnatal life, but their role in brain development remains to be elucidated. We now report that mGlu5^−/− mice showed a large reduction in mRNA and protein levels of myelin-associated glycoprotein (MAG), myelin oligodendrocyte glycoprotein (MOG), and myelin basic protein (MBP) in the cerebral cortex and cerebellum at postnatal day (PND) 14. Expression of these proteins reflects oligodendrocyte differentiation and myelin formation in the CNS, a process that is prominent in the second week of postnatal life in mice. Expression of myelin markers recovered at later developmental stages, with the exception of MAG and MBP levels in the cerebellum, which were still reduced in mGlu5^−/− mice. We also observed a large reduction in myelin protein markers in the cerebral cortex and cerebellum of mice treated with the mGlu5 receptor negative allosteric modulator MTEP (3 mg/kg, i.p.) from PND 7 to PND 14. MTEP-treated mice also showed reduced motor coordination and sensorimotor function at PND 14. Treatment with MTEP reduced oligodendrocyte maturation without affecting proliferation of oligodendrocyte progenitor cells in primary cultures prepared from the rat cerebral cortex. These findings suggest that endogenous activation of mGlu5 receptors contributes to myelin formation during postnatal development in mice. Full article

Cerebellar climbing fiber–Purkinje cell (CF–PC) long-term depression (LTD) plays a critical role in motor learning and is modulated by locus coeruleus (LC) noradrenergic afferents via distinct adrenergic receptor (AR) subtypes. Nevertheless, the mechanisms underlying LC noradrenergic neuron-mediated regulation of CF–PC LTD remain poorly understood. Here, we investigated the effects of chemogenetic activation of LC noradrenergic afferents on CF–PC LTD in cerebellar slices from dopamine β-hydroxylase (DBH)-Cre mice using electrophysiology, glutamate sensor imaging, immunofluorescence and pharmacological approaches. Tetanic stimulation (5 Hz) of CFs induced CF–PC LTD under control conditions, and this LTD was enhanced by chemogenetic activation of LC noradrenergic afferents. Blockade of group I metabotropic glutamate receptors (mGluR1) abolished LTD under control conditions, whereas chemogenetic activation of LC noradrenergic afferents triggered a novel form of CF–PC LTD accompanied by an increased N2/N1 ratio. With mGluR1 blocked, chemogenetic activation of LC noradrenergic afferents failed to trigger the novel CF–PC LTD following blockade of α₂-AR or α₂A-AR, but not α₂B-AR or α₂C-AR. Importantly, chemogenetic activation of LC noradrenergic afferents triggered LTD of glutamate fluorescence at CF terminals, which was abolished by blockade of α_2-AR or α₂A-AR, but not α₂B-AR or α₂C-AR. Notably, inhibition of either cyclin-dependent kinase 5 (CDK5) or presynaptic, but not postsynaptic, protein kinase A (PKA) completely abolished the CF–PC LTD triggered by chemogenetic activation of LC noradrenergic afferents in mouse cerebellar slices. Immunofluorescence results showed robust α₂A-AR expression throughout the cerebellar molecular layer, with intense signals along PC dendrites and clear colocalization with vesicular glutamate transporter 2 (vGluT2) at cerebellar CF terminals. These results indicate that activation of LC noradrenergic afferents potentiates CF–PC LTD by triggering Glu-LTD at CF terminals through the α₂A-AR/CDK5/PKA signaling cascade in the mouse cerebellar cortex. Full article

The autism spectrum disorder-associated SCN2A, ANK2, and SHANK-family genes encode molecularly distinct proteins that converge functionally on dendritic integration. Recent work established that ankyrin-B, encoded by ANK2, acts as an obligate dendritic scaffold for NaV1.2, encoded by SCN2A, in neocortical pyramidal neurons. Loss of this module mislocalizes dendritic NaV1.2, reduces dendritic Na⁺ influx, weakens backpropagating action potentials, and impairs synaptic maturation and long-term potentiation. SHANK proteins organize a complementary postsynaptic receptor scaffold within dendritic spines, coupling N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and metabotropic glutamate receptor (e.g., mGluR5) signaling to the actin cytoskeleton through layered PSD-95/GKAP/Homer interactions. Disruption of this scaffold can destabilize excitatory transmission, spine morphology, and plasticity. We propose that these dendritic shaft and spine-associated modules jointly regulate dendritic input–output gain and that their disruption may contribute to autism spectrum disorder by destabilizing, rather than uniformly shifting, excitatory integration across cortico-subcortical circuits relevant to sensory reactivity, behavioral flexibility, and social-valence processing. Here, we review the cortical evidence for this layered dendritic convergence and evaluate its potential relevance beyond the cortex. We assess the striatum, thalamus, and amygdala as subcortical sites where related dendritic scaffolding mechanisms may operate. The striatum provides the strongest current test case, with established roles for both NaV1.2 and SHANK3 in medium spiny neuron physiology and corticostriatal connectivity. Thalamic and amygdalar extensions are supported mainly by SHANK-related circuit and channelopathy data but lack direct evidence for ANK2–SCN2A involvement. The framework is experimentally testable: conditional Ank2 deletion in striatal, thalamic, and amygdalar cell types; dendritic Na⁺/Ca²⁺ imaging across Scn2a, Ank2, and Shank3 models; adult rescue experiments; and genetic-interaction designs would determine whether ankyrin-B supports dendritic excitability beyond the cortex and whether these genes converge on, rather than merely parallel, dendritic input–output gain. Validation in human subcortical tissue would then establish whether this dendritic scaffolding logic represents a shared point of convergence through which genetically distinct autism spectrum disorder-risk variants alter circuit function. Full article

Background/Objectives: Persistent cognitive impairments are prevalent in methamphetamine (meth) use disorder and contribute to maladaptive decision-making and increased relapse vulnerability. There are currently no effective treatments for meth-associative cognitive deficits, and their neurobiological underpinnings remain incompletely understood. This study investigated the effects of chronic meth self-administration on episodic-like recognition memory and evaluated whether pharmacological potentiation of metabotropic glutamate receptor subtype 2 (mGlu2) could rescue these deficits. Methods: Adult male Long–Evans rats underwent 7 days of limited- (1 h/day) followed by 14 days of extended-access (6 h/day) meth self-administration, followed by 30 days of abstinence. Recognition memory was assessed using the object-in-place (OIP) task. A positive allosteric modulator of mGlu2 receptors, LY-487379 (25 mg/kg, s.c.), was administered prior to the memory test. In parallel, changes in total and surface mGlu2/3 protein levels in the prelimbic and perirhinal cortices were evaluated. Results: Rats with extended access to meth self-administration exhibited escalated drug intake and persistent deficits in OIP memory. Administration of LY-487379 acutely rescued this deficit. Total mGlu2/3 protein levels were unaltered; however, meth exposure was associated with a significant increase in surface mGlu2/3 receptor expression in both cortical regions examined. Conclusions: These results demonstrate that chronic meth produces persistent cognitive dysfunction that can be rescued by mGlu2 receptor potentiation. The observed increase in surface mGlu2/3 expression may represent a compensatory response to chronic glutamatergic dysregulation, but it appears to be insufficient to restore cognitive function alone, without pharmacological enhancement. The current data encourage further exploration of mGlu2’s role in stimulant-associated cognitive dysfunction. Full article

Hepatocellular carcinoma (HCC) is the most common type of liver cancer that is mostly preceded by cirrhosis, with a high mortality rate. Therefore, diagnosis is critical in the early stages. In this study, we explored the liver expression of metabotropic glutamate receptor 3 (mGluR3), a group II mGluR, during the progression from fibrosis to cirrhosis and, ultimately, to HCC induced by diethylnitrosamine (DEN) in rats. We found that mRNA expression of mGluR3 (Grm3) was upregulated in HCC, while the protein level was significantly increased from the cirrhosis stage, and even more in HCC. Grm3 correlated with interleukin-6 (Il6) and transforming growth factor-β (Tgfb) mRNA expression. Furthermore, serum and intrahepatic glutamate concentrations were augmented in HCC. Immunohistochemical analysis revealed that mGluR3 is expressed in hepatocytes and non-parenchymal cells (endothelial cells and macrophages), and we observed a positive signal in the cytoplasmic membrane, cytoplasm, and nuclei of tumor and non-tumor cells. We confirmed that normal hepatocytes (C9 cell line) express low levels of mGluR3 protein and HCC-derived cells (HepG2) express high levels of this receptor. Using HepG2 cells, we observed that mGluR3 activation by glutamate and the group II-selective agonist LY354740 treatments were functional, as both inhibited cAMP generation induced by forskolin and increased cellular viability with no effect on dead cells. These results showed that mGluR3 is differentially expressed throughout the progression of liver pathologies, is associated with the inflammatory environment, and plays a role in HCC cell survival, with potential utility as an early biomarker and therapeutic target. Full article

Glutamate metabotropic receptors (mGluRs) and their molecular partners at the postsynaptic density (PSD) represent a highly dynamic molecular hub that integrates multiple neurotransmitter signals and regulates synaptic plasticity and metaplasticity, which are putatively involved in the pathophysiology of psychiatric illnesses, including schizophrenia. Group I mGluRs (mGluR1 and mGluR5) interact with PSD adaptor and scaffolding proteins, such as Homer, Shank, Norbin, and PICK1, as well as intracellular downstream effectors, creating a molecular network that resembles a Lego-like structure, where modular protein interactions fine-tune glutamatergic transmission. Evidence from preclinical research indicates that dysregulation of mGluR expression and function, along with disrupted PSD protein expression, may contribute to the pathophysiology of schizophrenia by altering glutamatergic neurotransmission and synaptic stability. Antipsychotic mechanisms of action may involve, at least in part, the modulation of mGluR activity mediated through PSD proteins. Notably, novel agents that enhance spinogenesis by acting at the level of PSD proteins, such as SPG302, may open promising avenues for therapeutics aimed at restoring synaptic integrity. While Group I mGluRs dominate postsynaptic regulation, Group II (mGluR2/3) and III (mGluR4/6/7/8) receptors -primarily presynaptic- inhibit neurotransmitter release and plasticity, offering complementary therapeutic avenues. Emerging strategies, such as allosteric modulators of mGluRs, aim to rebalance synaptic signaling in treatment-resistant schizophrenia. This review synthesizes how PSD proteins and mGluRs interact in schizophrenia, exploring their potential as druggable targets for novel therapies. Full article

The incidence and mortality rates of lung adenocarcinoma (LUAD) continue to rise, highlighting an urgent need for novel therapeutic targets. In this study, bioinformatics analysis revealed that members of the metabotropic glutamate receptor (mGluR) family are significantly correlated with the expression profile, prognosis, genetic mutations, and tumor immune microenvironment of LUAD, with GRM5 being the most significantly associated member. Overexpression of GRM5 has been shown to inhibit LUAD proliferation and induce apoptosis, while cinchonine (CN) treatment further enhances these effects, suggesting that CN may act as a GRM5 agonist to synergistically exert antitumor activity. Transcriptome sequencing further identified four key downstream targets and their associated signaling pathways. In summary, this study confirms that GRM5 can serve as a potential prognostic biomarker and therapeutic target for LUAD, while the small-molecule compound CN shows promise as an antitumor candidate drug targeting GRM5. Full article

Background/Objectives: The neurotransmitter glycine is involved in several physiological and pathological conditions in the Central Nervous System. Different biological structures, including glycine receptors and transporters, are under study as targets for potential drugs acting against serious neurological and psychiatric disorders. The regulation of glycine release from nerve terminals is only partially understood. We report here preliminary evidence of the modulation of glycine release through presynaptic metabotropic glutamate receptors 1 (mGlu1) from glycinergic nerve terminals in mouse hippocampi. Methods: Purified mouse hippocampal synaptosomes labeled with [³H]glycine were used to study glycine release under superfusion conditions. Results: The group I metabotropic glutamate receptor agonist 3,5-DHPG potentiated depolarization-evoked [³H]glycine release from hippocampal synaptosomes, an effect strongly counteracted by the selective mGlu1 antagonist LY 367385. 3,5-DHPG failed to increase [³H]glycine release in Grm1^crv4/crv4 mice, a mouse model lacking mGlu1. Although further research is needed to clarify these mechanisms, data suggest that glycine-releasing hippocampal nerve terminals are endowed with presynaptic mGlu1 receptors whose activation potentiates glycine release. Conclusions: Considering that in the hippocampus, glycine is relevant as a co-agonist of glutamate at NMDA receptors and that mGlu1 receptor ligands are under study as potential drugs, we propose that the possible effects of these agents on the release of glycine should be considered when studying these compounds. Full article

Since the introduction of the NMDA receptor antagonist (S)-ketamine for depression therapy, it has become evident that the glutamatergic hypothesis of depression, proposed over 20 years ago, was justified and based on solid foundations. A significant breakthrough with this drug is its ability to produce a rapid and relatively long-lasting antidepressant effect in patients who are resistant to traditional depression treatments, both pharmacological and non-pharmacological. However, alongside its beneficial effects, (S)-ketamine can cause several side effects that make it a less safe option. As a result, strategies are being explored to mitigate the risks associated with its use. These strategies include leveraging the shared mechanism of action between ketamine and various modulators of the glutamatergic system. Preclinical studies have shown that low doses of mGlu₂ and mGlu₅ receptor antagonists can enhance the therapeutic effects of ketamine or its enantiomers without producing the typical side effects associated with ketamine. This review discusses the research on this synergistic effect, the underlying mechanisms, and the role of mGlu₂ and mGlu₅ receptors in the antidepressant action of ketamine. Full article

Glutamine addiction in human melanoma is a premier example of the cancer hallmark of metabolic reprogramming. In the present study, we investigate the presence of metabotropic glutamate receptor 1 (mGluR1/GRM1) and glutaminase (GLS1/GLS) in canine oral malignant melanoma (OMM) and those of low malignant potential, termed histologically well-differentiated melanocytic neoplasm of the lips and oral mucosa (HWDMN). We used immunohistochemistry (IHC) and qPCR to evaluate mGluR1 and GLS1 protein expression and RNA expression, respectively. Nearly 20% of OMM cases had an mGluR1 IHC score ≥ 1, while none of the HWDMN cases had any expression. Due to low IHC expression, only 10 cases were selected for determination of GRM1 RNA expression, and none were positive. GLS RNA expression did not differ between OMM and HWDMN. A GLS1 IHC score ≥ 1 was significantly higher in OMM cases and highly specific (95%) for correctly identifying tumors with a Ki67 index ≥ 19.5. These results may have been negatively impacted by use of a brown chromogen for IHC labeling among background pigment, particularly in HWDMN. Ultimately, these findings suggest that canine OMM does not heavily rely on mGluR1 for tumorigenesis or progression. Differential GLS1 protein expression warrants further investigation with protein quantification. Full article

Glutamate-related excitotoxicity represents a fundamental pathological process underlying both acute and chronic disorders of the central nervous system. Excessive stimulation of ionotropic and metabotropic glutamate receptors induces ionic dysregulation, mitochondrial dysfunction, and oxidative stress, which can activate necrotic and apoptotic pathways, processes further amplified by defective glutamate clearance and astrocytic impairment. These mechanisms are recognized as key contributors to neuronal damage in ischemic stroke, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, identifying excitotoxicity as a convergent hallmark of neurodegeneration. Despite considerable progress in elucidating its molecular mechanisms, clinical translation of excitotoxicity-targeted interventions remains limited, largely due to the difficulty of selectively attenuating pathological glutamatergic activity while preserving physiological neurotransmission. Recent advances in nanotechnology, particularly the development of graphene-based materials (GBMs), have offered innovative approaches for neuroprotection. Owing to their unique physicochemical properties and compatibility with neural tissue, GBMs have been investigated as platforms for neural interfacing, regenerative scaffolds, drug delivery platforms, and direct modulators of glutamatergic transmission. In particular, small graphene oxide nanosheets exhibit the capacity to downregulate glutamate release and confer anti-inflammatory and neuroprotective effects. These findings suggest that GBMs may represent a promising class of neuromodulatory tools for mitigating excitotoxic injury, warranting further preclinical and translational investigations. Full article

Febrile seizures (FS) are a common childhood neurological event associated with an increased risk of long-term cognitive and emotional deficits, though the precise mechanisms remain elusive. Using a rat model, we investigated the long-term effects of FS induced on postnatal day 10, assessing outcomes in young adulthood (P45-55). We report region-specific neuronal loss in the hippocampus, more extensive in the ventral segment. Molecular analysis revealed a broad downregulation of genes encoding ionotropic and metabotropic glutamate receptors and excitatory amino acid transporters. These alterations were most severe and persistent in the ventral hippocampus and medial prefrontal cortex. Behaviorally, rats with neonatal FS exhibited a hyperanxious phenotype, characterized by reduced locomotor and exploratory activity and impaired habituation to a novel environment. In contrast, spatial working memory and social behavior remained intact. Our results provide the first comprehensive evidence that neonatal FS trigger long-term, region-specific disruptions of the glutamatergic system within hippocampal–prefrontal circuits. These findings identify vulnerable molecular targets and precise neurobiological mechanisms that may underlie the heightened risk of anxiety-related disorders following early-life FS, suggesting new avenues for therapeutic intervention. Full article

The black-lip rock oyster, Saccostrea echinata, is an emerging aquaculture species; however, difficulties in regulating their gonad conditioning to full maturation and spawning have impacted industry progress. Addressing this challenge requires a deeper understanding of the molecular mechanisms underlying reproduction, particularly the signalling molecules (e.g., neuroendocrine hormones) that regulate gonad development and spawning, which remains poorly understood in this species. Therefore, we investigated the molecular neuroendocrine regulation of gonad maturation in S. echinata through the analysis of gonad histological changes correlated with gene expression in the visceral ganglia and gonad (of male and female) at pre- and post-spawn stages. Our targeted analysis of neuropeptide genes demonstrated that only LASGLVamide showed significant differential expression, being upregulated in the pre-spawn female gonad. Of the 26 reproductive-related genes identified, four were significantly upregulated in female gonad (SOX9, Dax1, Nanos-like, and Piwi-like), while an insulin-like peptide receptor was elevated in male visceral ganglia at post-spawn. Untargeted investigation revealed numerous transmembrane receptors significantly upregulated in the pre-spawn ovary, such as receptors for thyrotropin-releasing hormone, metabotropic glutamate, and 5-hydroxytryptamine, while mesotocin and oxytocin receptors were upregulated in pre-spawn male gonads. At the post-spawn stage, the visceral ganglia displayed upregulation of genes encoding stress-related proteins such as superoxidase dismutase and DnaJ homologue subfamily A member 1. These findings provide important insights into the complexities of neuroendocrine signalling molecules and establish a molecular foundation to guide selective breeding and broodstock management strategies that will support sustainable aquaculture development of black-lip rock oyster. Full article

Extensive research has focused on developing anti-nociceptive therapy by targeting specific molecular pathways. Among these, the serotonin 2A receptor (5-HT2AR) and metabotropic glutamate receptor 5 (mGluR5) are recognized as key mediators of neuropathic pain. However, the therapeutic potential of their simultaneous inhibition remains largely unexplored. In this study, we evaluated the efficacy of dual antagonism of 5-HT2AR and mGluR5 using spinal nerve ligation (SNL) and formalin-induced pain models in male Sprague–Dawley rats. Co-administration of selective antagonists significantly enhanced anti-allodynic and anti-nociceptive effects, as evidenced by increased withdrawal thresholds and reduced pain-related behaviors compared to monotherapy. The analgesic efficacy of dual antagonism was comparable to that of gabapentin and morphine. Additionally, novel small molecules designed to concurrently inhibit 5-HT2AR and mGluR5 exerted dose-dependent anti-nociceptive effects by suppressing excitatory postsynaptic responses and inhibiting the phosphorylation of ERK and AKT signaling molecules. Importantly, unlike morphine, repeated administration of the dual antagonist maintained anti-allodynic efficacy with a low potential of abuse. These findings may indicate the promise of simultaneous 5-HT2AR and mGluR5 antagonism as a novel and potentially safer strategy for managing chronic neuropathic pain. Full article

Feline calicivirus (FCV) is among the few members of the Caliciviridae family that can replicate efficiently in vitro. Our recent studies have found the Transferrin Receptor Protein (TFRC) is an entry receptor that facilitates the internalization of FCV. To explore the potential involvement of additional host factors in conjunction with TFRC during the viral entry process, we identified metabotropic glutamate receptor 2 (mGluR2) as a specific interacting partner for both TFRC and the FCV VP1 protein by Co-IP analysis. Our findings indicate that the downregulation of mGluR2, along with its downstream signaling molecule, Calcium-activated potassium channel subunit alpha-1 (KCa1.1), significantly inhibits FCV replication by impairing viral internalization. Importantly, the knockout of TFRC did not diminish the effects of mGluR2 and KCa1.1 on FCV infection. Furthermore, mGluR2 was found to interact directly with FCV VP1, rather than with TFRC, and the rate of F-actin polymerization induced by FCV infection was reduced solely by the downregulation of mGluR2 protein expression, not by TFRC knockout. These results suggest that mGluR2 may independently mediate FCV internalization, operating independently of TFRC, and plays a critical role in the formation of endocytic vesicles. Overall, the results indicate that multiple host factors, including TFRC and mGluR2, are involved in the internalization of FCV into host cells. Further research is necessary to explore the propagation of other caliciviruses, such as norovirus, in vitro. Full article