Search Results (62)

Metabotropic glutamate receptor 5 (mGlu₅) plays a fundamental role in synaptic plasticity, potentially serving as a therapeutic target for various neurodevelopmental and psychiatric disorders. Previously, we have shown that mGlu₅ can also signal from intracellular membranes in the cortex, hippocampus, and striatum. Using cytoplasmic Ca²⁺ indicators, we showed that activated cell surface mGlu₅ induced a transient Ca²⁺ increase, whereas the activation of intracellular mGlu₅ mediated a sustained Ca²⁺ elevation in striatal neurons. Here, we used the newly designed ER-targeted Ca²⁺ sensor, ER-GCaMP6-150, as a robust, specific approach to directly monitor mGlu₅-mediated changes in ER Ca²⁺ itself. Using this sensor, we found that the activation of cell surface mGlu₅ led to small declines in ER Ca²⁺, whereas the activation of ER-localized mGlu₅ resulted in rapid, more pronounced changes. The latter could be blocked by the Gq inhibitor FR9000359, the PLC inhibitor U73122, as well as IP₃ and ryanodine receptor blockers. These data demonstrate that like cell surface and nuclear mGlu₅, ER-localized receptors play a pivotal role in generating and shaping intracellular Ca²⁺ signals. Full article

Metabotropic glutamate receptor 5 (mGluR5) is a critical regulator of immune responses within the neuroimmune system, influencing cytokine secretion and immune cell function. Although extensively studied in mammals, its role in regulating IL-17 in invertebrate immunity is poorly understood. This study examines CgmGluR5 expression and downstream signaling activation in Pacific oyster (Crassostrea gigas) hemocytes following glutamate (Glu) and Vibrio splendidus treatment. Glu treatment significantly induced the expression of CgmGluR5 and key signaling molecules, including PLC, DAG, IP3, Ca²⁺, and PKC, while enhancing mRNA levels of CgIL17-1, CgIL17-5, and CgCaspase3. Elevated Ca²⁺ content and CgIL17 expression in hemocytes were observed at 12 h post-Glu exposure, indicating CgmGluR5-mediated immune regulation through the phosphoinositide pathway. A 1.14-fold increase in the apoptosis rate was found in the Glu treatment group compared to the control group. Knockdown of CgmGluR5 suppressed CgIL17-1 and CgIL17-5 expression and reduced granulocyte proportions, reflecting its role in immune regulation. This study shows that CgmGluR5 mediates long-term immune regulation in oysters through the phosphoinositide pathway, providing new theoretical insights for aquaculture immune management. Full article

Background/Objectives: Non-response to initial treatment options for major depressive disorder (MDD) is a common clinical challenge with profound deleterious impacts for affected patients. Few treatments have received regulatory approval for treatment-resistant depression (TRD). Methods: A systematic search of United States and European Union clinical trials registries was conducted to identify Phase II, III, or IV clinical trials, with a last update posted on or after 1 January 2020, that were evaluating medications for TRD. For both the US and EU registries, the condition term “treatment resistant depression” and associated lower-level terms (per registry search protocol) were used. For the US registry, a secondary search using the condition term “depressive disorders” and the modifying term “inadequate” was also performed to capture registrations not tagged as TRD. Two additional searches were also conducted in the US registry for the terms “suicide” and “anhedonia” as transdiagnostic targets of investigational medications. Trials were categorized based on the primary mechanism of action of the trial’s investigational medication. Results: Fifty clinical trials for TRD, 20 for anhedonia, and 25 for suicide were identified. Glutamate system modulation was the mechanism currently with the most compounds in development, including antagonists and allosteric modulators of NMDA receptors, AMPA receptors, metabotropic type 2/3 glutamate receptors, and intracellular effector molecules downstream of glutamate signaling. Psychedelics have seen the greatest surge among mechanistic targets in the past 5 years, however, with psilocybin in particular garnering significant attention. Other mechanisms included GABA modulators, monoamine modulators, anti-inflammatory/immune-modulating agents, and an orexin type 2 receptor antagonist. Conclusions: These investigations offer substantial promise for more efficacious and potentially personalized medication approaches for TRD. Challenges for detecting efficacy in TRD include the heterogeneity within the TRD population stemming from the presumed variety of biological dysfunctions underlying the disorder, comorbid disorders, chronic psychosocial stressors, and enduring effects of prior serotonergic antidepressant medication treatments. Full article

The metabotropic glutamate receptor type 5 (mGlu5) and adenosine A(2A) receptor form a mutually inhibitory heteromer with the dopamine D2 receptor, where the activation of either mGlu5 or A(2A) leads to reduced D2 signaling. This study investigated whether a mGlu5-positive allosteric modulator (PAM) or an A(2A) agonist treatment could mitigate sensorimotor gating deficits and alter cyclic AMP response element-binding protein (CREB) levels in a rodent neonatal quinpirole (NQ) model of psychosis. F0 Sprague–Dawley rats were treated with neonatal saline or quinpirole (1 mg/kg) from postnatal day 1 to 21 and bred to produce an F1 generation. F1 offspring underwent prepulse inhibition (PPI) testing from postnatal day 44 to 48 to assess sensorimotor gating. The rats were treated with mGlu5 PAM 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB) or A(2A) agonist CGS21680. Rats with at least one NQ-treated parent showed PPI deficits, which were alleviated by both CDPPB and CGS21680. Sex differences were noted across groups, with CGS21680 showing greater efficacy than CDPPB. Additionally, CREB levels were elevated in the nucleus accumbens (NAc), and both CDPPB and CGS21680 reduced CREB expression to control levels. These findings suggest that targeting the adenosinergic and glutamatergic systems alleviates sensorimotor gating deficits and abnormal CREB signaling, both of which are associated with psychosis. Full article

Provoked vulvodynia (PV) is the leading cause of vulvar pain and dyspareunia. The etiology of PV is multifactorial and remains poorly understood. PV is associated with a history of repeated vulvar inflammation and is often accompanied by sensory neuromodulation as a result of activation of the metabotropic glutamate receptor 5 (mGluR5) in the sensory nerve terminals. Therefore, this study aims to examine the role of glutamate-mGluR5 signaling during the initial inflammatory phase in chronic vulvar pain development in an animal model of PV.Thermal and mechanical vulvar sensitivity was assessed for three weeks following zymosan vulvar challenges. Anxiety-like behavior and locomotor activity were assessed at the end of the experiment. To investigate the role of glutamate mGluR5, the MTEP (mGluR5 antagonist) was injected into the vulva during vulvar inflammation. On the other hand, glutamate or CHPG (mGluR5 agonist) were injected in order to examine the effects of mGluR5 activation. RT-PCR was performed to assess changes in the transcription of genes related to neuroinflammation, neuromodulation, and neuroplasticity in the spinal cord (L6-S3). Zymosan-induced inflammation resulted in a significant thermal and mechanical vulvar hypersensitivity that persisted for over a month after the zymosan injection. However, local treatment with MTEP enhanced the vulvar mechanical and thermal hypersensitivity. On the other hand, activation of the mGluR5 via injection of glutamate or CHPG into the vulva leads to long-lasting vulvar mechanical and thermal hypersensitivity. The activation of the glutamate pathway was found to be accompanied by an increase in the transcription level of genes related to neuroinflammation and neuroplasticity in the sacral spine region. The present findings indicate that vulvar hypersensitivity is mediated by mGluR5 activation during inflammation. Hence, modulation of the mGluR5 pathway during the critical period of inflammation contributes to preventing chronic vulvar pain development. Conversely, activation of the mGluR5 pathway leads to long-lasting mechanical and thermal hypersensitivity. Full article

Autoantibodies targeting the neuronal antigen metabotropic glutamate receptor 5 (mGluR5) have been identified in patients with Ophelia syndrome, which describes a co-occurrence of paraneoplastic limbic encephalitis and Hodgkin lymphoma (HL). Little data exist regarding frequency and function of mGluR5 in HL and its potential role in causing seropositive paraneoplastic disease. We studied a representative cohort of pediatric HL and NHL patients (n = 57) using immunohistochemistry and fluorescence staining to investigate mGluR5 expression. All lymphoma tissues displayed positive mGluR5 staining, with focus on Hodgkin–Reed–Sternberg (H-RS) cells. We did not detect any mGluR5 staining in tumor-free lymph nodes, which is consistent with the absence of GRM5 transcripts in RNA-sequencing data from non-malignant B and T cells. The frequent presence in pediatric lymphoma falls in line with reports of mGluR5 expression and associated tumor progression in other malignancies. We tested for correlation with clinical features, focusing on disease progression and neurological symptoms. Low mGluR5 expression in H-RS cells correlated with young patient age (<15 years) and positive histology for EBV infection. Paraneoplastic or neurological symptoms were found exclusively in HL patients. While an impact of mGluR5 on HL severity remains possible, a prognostic value of mGluR5 expression levels requires further investigation. Full article

High-frequency magnetic stimulation (HFMS) applied directly to the hippocampal slice preparation in vitro induces activity-dependent synaptic plasticity and metaplasticity. In addition, changes in synaptic transmission following HFMS involve the activation of N-methyl-D-aspartate and metabotropic glutamate receptors (mGluR). Here, we asked whether a short period of HFMS (5 × 10 delta-burst trains, duration of ~1 min) could alter mGluR5-mediated depression at Schaffer collateral–CA1 synapses in the acute brain slice preparation at 30 min after HFMS. To this end, we obtained field excitatory postsynaptic potential (fEPSP) slopes from Schaffer collateral–CA1 synapses after HFMS or control. First, we demonstrated that activity-dependent plasticity following HFMS depends on the slice orientation towards the magnetic coil indicating specific ion fluxes induced by magnetic fields. Second, we found that the mGluR5-specific agonist (RS)-2-chloro-5-hydroxyphenylglycine reduced the field excitatory postsynaptic potential (fEPSP) slopes in control slices but rather enhanced them in HFMS-treated slices. In contrast, the compound (S)-3,5-dihydroxyphenylglycine acting at both mGluR1 and mGluR5 reduced fEPSP slopes in both control and HFMS-treated slices. Importantly, the mGluR-dependent effects were independent from the slice-to-coil orientation indicating that asynchronous glutamate release could play a role. We conclude that a short period of HFMS inhibits subsequently evoked mGluR5-dependent depression at Schaffer collateral–CA1 synapses. This could be relevant for repetitive transcranial magnetic stimulation in psychiatric disorders such as major depression. Full article

Chronic opioid treatments dysregulate the glutamatergic system, inducing a hyperglutamatergic state in mesocorticolimbic brain regions. This study investigated the effects of exposure to hydrocodone overdose on locomotor activity, expression of target proteins related to the glutamatergic system, signaling kinases, and neuroinflammatory factors in the nucleus accumbens. The locomotor activity of mice was measured using the Comprehensive Laboratory Animal Monitoring System (CLAMS). CLAMS data showed that exposure to hydrocodone overdose increased locomotion activity in mice. This study tested ceftriaxone, known to upregulate major glutamate transporter 1 (GLT-1), in mice exposed to an overdose of hydrocodone. Thus, ceftriaxone normalized hydrocodone-induced hyperlocomotion activity in mice. Furthermore, exposure to hydrocodone overdose downregulated GLT-1, cystine/glutamate antiporter (xCT), and extracellular signal-regulated kinase activity (p-ERK/ERK) expression in the nucleus accumbens. However, exposure to an overdose of hydrocodone increased metabotropic glutamate receptor 5 (mGluR5), neuronal nitric oxide synthase activity (p-nNOS/nNOS), and receptor for advanced glycation end products (RAGE) expression in the nucleus accumbens. Importantly, ceftriaxone treatment attenuated hydrocodone-induced upregulation of mGluR5, p-nNOS/nNOS, and RAGE, as well as hydrocodone-induced downregulation of GLT-1, xCT, and p-ERK/ERK expression. These data demonstrated that exposure to hydrocodone overdose can cause dysregulation of the glutamatergic system, neuroinflammation, hyperlocomotion activity, and the potential therapeutic role of ceftriaxone in attenuating these effects. Full article

Acting as GTPase activating proteins promoting the silencing of activated G-proteins, regulators of G protein signaling (RGSs) are generally considered negative modulators of cell signaling. In the CNS, the expression of RGS4 is altered in diverse pathologies and its upregulation was reported in astrocytes exposed to an inflammatory environment. In a model of cultured cortical astrocytes, we herein investigate the influence of RGS4 on intracellular calcium signaling mediated by type 5 metabotropic glutamate receptor (mGluR5), which is known to support the bidirectional communication between neurons and glial cells. RGS4 activity was manipulated by exposure to the inhibitor CCG 63802 or by infecting the cells with lentiviruses designed to achieve the silencing or overexpression of RGS4. The pharmacological inhibition or silencing of RGS4 resulted in a decrease in the percentage of cells responding to the mGluR5 agonist DHPG and in the proportion of cells showing typical calcium oscillations. Conversely, RGS4-lentivirus infection increased the percentage of cells showing calcium oscillations. While the physiological implication of cytosolic calcium oscillations in astrocytes is still under investigation, the fine-tuning of calcium signaling likely determines the coding of diverse biological events. Indirect signaling modulators such as RGS4 inhibitors, used in combination with receptor ligands, could pave the way for new therapeutic approaches for diverse neurological disorders with improved efficacy and selectivity. Full article

The role of endothelial nitric oxide synthase (eNOS) in the regulation of a variety of biological processes is well established, and its dysfunction contributes to brain pathologies, including schizophrenia or Alzheimer’s disease (AD). Positive allosteric modulators (PAMs) of metabotropic glutamate (mGlu) receptors were shown to be effective procognitive compounds, but little is known about their impact on eNOS expression and stability. Here, we investigated the influence of the acute and chronic administration of LY487379 or CDPPB (mGlu2 and mGlu5 PAMs), on eNOS expression in the mouse brain and the effect of the joint administration of the ligands with nitric oxide (NO) releasers, spermineNONOate or DETANONOate, in different combinations of doses, on MK-801- or scopolamine-induced amnesia in the novel object recognition (NOR) test. Our results indicate that both compounds provoked eNOS monomer formation, and CDPPB at a dose of 5 mg/kg exaggerated the effect of MK-801 or scopolamine. The coadministration of spermineNONOate or DETANONOate enhanced the antiamnesic effect of CDPPB or LY487379. The best activity was observed for ineffective or moderate dose combinations. The results indicate that treatment with mGluR2 and mGluR5 PAMs may be burdened with the risk of promoting eNOS uncoupling through the induction of dimer dissociation. Administration of the lowest possible doses of the compounds with NO^• donors, which themselves have procognitive efficacy, may be proposed for the treatment of schizophrenia or AD. Full article

Background: Metabotropic glutamate receptors type 5 (mGluR5) play a central role in persistent forms of synaptic plasticity and memory formation. Antibodies to mGluR5 have been reported to be clinically associated with memory impairment. Here, we report on a patient with persistent amnestic cognitive impairment in a single cognitive domain after resolution of mGluR5-associated encephalitis. Methods: We report on the clinical data of a patient in our Department of Psychiatry and Psychotherapy who underwent several diagnostic investigations including a detailed neuropsychological examination, magnetic resonance imaging, and cerebrospinal fluid analysis involving the determination of neural autoantibodies. Results: A 54-year-old woman presented to our memory clinic with pleocytosis 4 months after remission of probable anti-mGluR5-mediated encephalitis, revealing initial pleocytosis and serum proof of anti-mGluR5 autoantibodies (1:32). A neuropsychological examination revealed mild cognitive impairment in verbal memory encoding and recall. The patient received immunotherapy with corticosteroids, and a subsequent cerebrospinal fluid analysis 1.5 months after the onset of encephalitis confirmed no further signs of inflammation. Conclusions: Our results suggest that although immunotherapy resulted in the remission of anti-mGluR5 encephalitis, a verbal memory encoding and recall dysfunction persisted. It remains unclear whether the reason for the persistent verbal memory impairment is attributable to insufficiently long immunotherapy or initially ineffective immunotherapy. Because mGluR5 plays an essential role in persistent synaptic plasticity in the hippocampus, it is tempting to speculate that the mGluR5 antibody–antigen complex could lead to persistent cognitive dysfunction, still present after the acute CNS inflammation stage of encephalitis. Full article

Concerns have been raised regarding the potential adverse health effects of the ubiquitous herbicide glyphosate. Here, we investigated long-term effects of developmental exposure to a glyphosate-based herbicide (GBH) by analyzing serum melatonin levels and cellular changes in the striatum of adult male rats (90 days old). Pregnant and lactating rats were exposed to 3% GBH (0.36% glyphosate) through drinking water from gestational day 5 to postnatal day 15. The offspring showed reduced serum melatonin levels (43%) at the adult age compared with the control group. The perinatal exposure to GBH also induced long-term oxidative stress-related changes in the striatum demonstrated by increased lipid peroxidation (45%) and DNA/RNA oxidation (39%) together with increased protein levels of the antioxidant enzymes, superoxide dismutase (SOD1, 24%), glutamate–cysteine ligase (GCLC, 58%), and glutathione peroxidase 1 (GPx1, 31%). Moreover, perinatal GBH exposure significantly increased the total number of neurons (20%) and tyrosine hydroxylase (TH)-positive neurons (38%) in the adult striatum. Mechanistic in vitro studies with primary rat pinealocytes exposed to 50 µM glyphosate demonstrated a decreased melatonin secretion partially through activation of metabotropic glutamate receptor 3 (mGluR3), while higher glyphosate levels (100 or 500 µM) also reduced the pinealocyte viability. Since decreased levels of the important antioxidant and neuroprotector melatonin have been associated with an increased risk of developing neurodegenerative disorders, this demonstrates the need to consider the melatonin hormone system as a central endocrine-related target of glyphosate and other environmental contaminants. Full article

Repeated maternal separation (MS) is a useful experimental model in rodents for studying the long-term influence of early-life stress on brain neurophysiology. In our work, we assessed the effect of repeated MS (postnatal day (PND)1–21, 180 min/day) on the postnatal development of rat brain regions involved in memory using proton magnetic resonance spectroscopy (¹HMRS) for tissue volume and the level of amino acids such as glutamate, aspartate, glutamine, glycine and gamma-aminobutyric acid (GABA) in the hippocampus. We assessed whether these effects are sex dependent. We also use novel object recognition (NOR) task to examine the effect of MS on memory and the effect of ethanol on it. Finally, we attempted to ameliorate postnatal stress-induced memory deficits by using VU-29, a positive allosteric modulator (PAM) of the metabotropic glutamate type 5 (mGlu5) receptor. In males, we noted deficits in the levels of glutamate, glycine and glutamine and increases in GABA in the hippocampus. In addition, the values of perirhinal cortex, prefrontal cortex and insular cortex and CA3 were decreased in these animals. MS females, in contrast, demonstrated significant increase in glutamate levels and decrease in GABA levels in the hippocampus. Here, the CA1 values alone were increased. VU-29 administration ameliorated these cognitive deficits. Thus, MS stress disturbs amino acids levels mainly in the hippocampus of adult male rats, and enhancement of glutamate neurotransmission reversed recognition memory deficits in these animals. Full article

Multiple studies have reported new or exacerbated persistent or resistant hypertension in patients previously infected with COVID-19. We used literature-based discovery to identify and prioritize multi-scalar explanatory biology that relates resistant hypertension to COVID-19. Cross-domain text mining of 33+ million PubMed articles within a comprehensive knowledge graph was performed using SemNet 2.0. Unsupervised rank aggregation determined which concepts were most relevant utilizing the normalized HeteSim score. A series of simulations identified concepts directly related to COVID-19 and resistant hypertension or connected via one of three renin–angiotensin–aldosterone system hub nodes (mineralocorticoid receptor, epithelial sodium channel, angiotensin I receptor). The top-ranking concepts relating COVID-19 to resistant hypertension included: cGMP-dependent protein kinase II, MAP3K1, haspin, ral guanine nucleotide exchange factor, N-(3-Oxododecanoyl)-L-homoserine lactone, aspartic endopeptidases, metabotropic glutamate receptors, choline-phosphate cytidylyltransferase, protein tyrosine phosphatase, tat genes, MAP3K10, uridine kinase, dicer enzyme, CMD1B, USP17L2, FLNA, exportin 5, somatotropin releasing hormone, beta-melanocyte stimulating hormone, pegylated leptin, beta-lipoprotein, corticotropin, growth hormone-releasing peptide 2, pro-opiomelanocortin, alpha-melanocyte stimulating hormone, prolactin, thyroid hormone, poly-beta-hydroxybutyrate depolymerase, CR 1392, BCR-ABL fusion gene, high density lipoprotein sphingomyelin, pregnancy-associated murine protein 1, recQ4 helicase, immunoglobulin heavy chain variable domain, aglycotransferrin, host cell factor C1, ATP6V0D1, imipramine demethylase, TRIM40, H3C2 gene, COL1A1+COL1A2 gene, QARS gene, VPS54, TPM2, MPST, EXOSC2, ribosomal protein S10, TAP-144, gonadotropins, human gonadotropin releasing hormone 1, beta-lipotropin, octreotide, salmon calcitonin, des-n-octanoyl ghrelin, liraglutide, gastrins. Concepts were mapped to six physiological themes: altered endocrine function, 23.1%; inflammation or cytokine storm, 21.3%; lipid metabolism and atherosclerosis, 17.6%; sympathetic input to blood pressure regulation, 16.7%; altered entry of COVID-19 virus, 14.8%; and unknown, 6.5%. Full article

Recent studies involving transplantation of feces from schizophrenia (SCZ) patients and their healthy controls into germ-free mice have demonstrated that the gut microbiome plays a critical role in mediating SCZ-linked physiology and behavior. To date, only one animal model (a metabotropic glutamate receptor 5 knockout) of SCZ has been reported to recapitulate SCZ-linked gut dysbiosis. Since human 22q11.2 microdeletion syndrome is associated with increased risk of SCZ, we investigated whether the 22q11.2 microdeletion (“Q22”) mouse model of SCZ exhibits both SCZ-linked behaviors and intestinal dysbiosis. We demonstrated that Q22 mice display increased acoustic startle response and ileal (but not colonic) dysbiosis, which may be due to the role of the ileum as an intestinal region with high immune and neuroimmune activity. We additionally identified a negative correlation between the abundance of a Streptococcus species in the ilea of Q22 mice and their acoustic startle response, providing early evidence of a gut–brain relationship in these mice. Given the translational relevance of this mouse model, our work suggests that Q22 mice could have considerable utility in preclinical research probing the relationship between gut dysbiosis and the gut–brain axis in the pathogenesis of SCZ. Full article