The Association between Blood Lymphocyte NMDAR, group I mGluRs and Cognitive Function Changes in Occupationally Aluminum-exposed Workers and Verification in Rats

Previous studies have implicated phospholipase C (PLC)-linked Group I metabotropic glutamate receptors (mGluRs) in regulating the excitability of hippocampal CA1 pyramidal neurons. We used intracellular recordings from rat hippocampal slices and specific antagonists to examine in more detail the mGluR receptor subtypes and signal transduction mechanisms underlying this effect. Application of the Group I mGluR agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) suppressed slow- and medium-duration afterhyperpolarizations (s- and mAHP) and caused a consequent increase in cell excitability as well as a depolarization of the membrane and an increase in input resistance. Interestingly, with the exception of the suppression of the mAHP, these effects were persistent, and in the case of the sAHP lasting for more than 1 h of drug washout. Preincubation with the specific mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), reduced but did not completely prevent the effects of DHPG. However, preincubation with both MPEP and the mGluR1 antagonist LY367385 completely prevented the DHPG-induced changes. These results demonstrate that the DHPG-induced changes are mediated partly by mGluR5 and partly by mGluR1. Because Group I mGluRs are linked to PLC via G-protein activation, we also investigated pathways downstream of PLC activation, using chelerythrine and cyclopiazonic acid to block protein kinase C (PKC) and inositol 1,4,5-trisphosphate-(IP3)-activated Ca2+ stores, respectively. Neither inhibitor affected the DHPG-induced suppression of the sAHP or the increase in excitability nor did an inhibitor of PLC itself, U-73122. Taken together, these results argue that in CA1 pyramidal cells in the adult rat, DHPG activates mGluRs of both the mGluR5 and mGluR1 subtypes, causing a long-lasting suppression of the sAHP and a consequent persistent increase in excitability via a PLC-, PKC-, and IP3-independent transduction pathway.

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Effects of Pet Insects on Cognitive Function among the Elderly: An fMRI Study

Journal of Clinical Medicine ◽

10.3390/jcm8101705 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1705 ◽

Cited By ~ 1

Author(s):

Ji-Yeon Park ◽

Hae-Jin Ko ◽

A-Sol Kim ◽

Ha-Na Moon ◽

Hye-In Choi ◽

...

Keyword(s):

Cognitive Function ◽

Elderly Women ◽

Wisconsin Card Sorting Test ◽

Community Dwelling ◽

Positive Effects ◽

Healthy Elderly ◽

Insect Rearing ◽

Group I ◽

Significant Difference ◽

Group Ii

Animal-assisted therapy has positive effects on cognitive function, depression, performance ability, and social functioning in elderly patients. The aim of this study was to evaluate the effects of rearing pet insects on the cognitive function of healthy elderly participants, with fMRI (functional magnetic resonance imaging) being used for this purpose. Community-dwelling right-handed elderly women (≥60 years) with normal cognitive function were enrolled and randomized at a 1:1 ratio into two groups: insect-rearing and control (n = 16) groups, with the insect-rearing group being further classified into two groups for analysis according to the subjects’ scores in the Wisconsin Card Sorting Test, WCST) at the baseline fMRI: Insect-rearing group I with a relatively high score (n = 13), and insect-rearing group II with a relatively low score (n = 6). The insect-rearing groups received and reared crickets as pet insects for 8 weeks. The WCST consisted of two variations, a high level baseline (HLB) and semi-WCST version. There was a significant difference accuracy of the HLB–semi-WCST (p < 0.05) in insect-rearing group II after 8 weeks from the baseline test. In the fMRI analysis involving the WCST reaction test, increased activation was observed in the right dorsal lateral prefrontal cortex and parietal cortex in insect-rearing group II when the semi-WCST, rather than the HLB, was performed. Rearing pet insects showed positive effects on executive functions and performance improvement in elderly women. Further larger studies on the effects of pet insects on cognitive function are warranted.

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Energetically optimized pharmacophore modeling to identify dual negative allosteric modulators against group I mGluRs in neurodegenerative diseases

Journal of Biomolecular Structure and Dynamics ◽

10.1080/07391102.2019.1640794 ◽

2019 ◽

Vol 38 (8) ◽

pp. 2326-2337 ◽

Cited By ~ 1

Author(s):

Sitrarasu Vijaya Prabhu ◽

Sanjeev Kumar Singh

Keyword(s):

Neurodegenerative Diseases ◽

Pharmacophore Modeling ◽

Allosteric Modulators ◽

Group I ◽

Group I Mglurs

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The post-synaptic scaffolding protein tamalin regulates ligand-mediated trafficking of metabotropic glutamate receptors

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.011979 ◽

2020 ◽

Vol 295 (25) ◽

pp. 8575-8588

Author(s):

Saurabh Pandey ◽

Namrata Ramsakha ◽

Rohan Sharma ◽

Ravinder Gulia ◽

Prachi Ojha ◽

...

Keyword(s):

Glutamate Receptors ◽

Protein Trafficking ◽

Hippocampal Neurons ◽

Metabotropic Glutamate Receptors ◽

Fragile X ◽

Critical Role ◽

Scaffolding Protein ◽

Metabotropic Glutamate ◽

Group I ◽

Group I Mglurs

Group I metabotropic glutamate receptors (mGluRs) play important roles in various neuronal functions and have also been implicated in multiple neuropsychiatric disorders like fragile X syndrome, autism, and others. mGluR trafficking not only plays important roles in controlling the spatiotemporal localization of these receptors in the cell but also regulates the activity of these receptors. Despite this obvious significance, the cellular machineries that control the trafficking of group I metabotropic glutamate receptors in the central nervous system have not been studied in detail. The post-synaptic scaffolding protein tamalin has been shown to interact with group I mGluRs and also with many other proteins involved in protein trafficking in neurons. Using a molecular replacement approach in mouse hippocampal neurons, we show here that tamalin plays a critical role in the ligand-dependent internalization of mGluR1 and mGluR5, members of the group I mGluR family. Specifically, knockdown of endogenous tamalin inhibited the ligand-dependent internalization of these two receptors. Both N-terminal and C-terminal regions of tamalin played critical roles in mGluR1 endocytosis. Furthermore, we found that tamalin regulates mGluR1 internalization by interacting with S-SCAM, a protein that has been implicated in vesicular trafficking. Finally, we demonstrate that tamalin plays a critical role in mGluR-mediated internalization of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, a process believed to be the cellular correlate for mGluR-dependent synaptic plasticity. Taken together, these findings reveal a mechanistic role of tamalin in the trafficking of group I mGluRs and suggest its physiological implications in the brain.

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Modulation of Neurological Deficits and Expression of Glutamate Receptors during Experimental Autoimmune Encephalomyelitis after Treatment with Selected Antagonists of Glutamate Receptors

BioMed Research International ◽

10.1155/2013/186068 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11 ◽

Cited By ~ 10

Author(s):

Grzegorz Sulkowski ◽

Beata Dąbrowska-Bouta ◽

Lidia Strużyńska

Keyword(s):

Experimental Autoimmune Encephalomyelitis ◽

Protein Expression ◽

Mrna Expression ◽

Glutamate Receptors ◽

Neurological Deficits ◽

Autoimmune Encephalomyelitis ◽

Protein Levels ◽

Group I ◽

Group I Mglurs ◽

Experimental Autoimmune

The aim of our investigation was to characterize the role of group I mGluRs and NMDA receptors in pathomechanisms of experimental autoimmune encephalomyelitis (EAE), the rodent model of MS. We tested the effects of LY 367385 (S-2-methyl-4-carboxyphenylglycine, a competitive antagonist of mGluR1), MPEP (2-methyl-6-(phenylethynyl)-pyridine, an antagonist of mGluR5), and the uncompetitive NMDA receptor antagonists amantadine and memantine on modulation of neurological deficits observed in rats with EAE. The neurological symptoms of EAE started at 10-11 days post-injection (d.p.i.) and peaked after 12-13 d.p.i. The protein levels of mGluRs and NMDA did not increase in early phases of EAE (4 d.p.i.), but starting from 8 d.p.i. to 25 d.p.i., we observed a significant elevation of mGluR1 and mGluR5 protein expression by about 20% and NMDA protein expression by about 10% over the control at 25 d.p.i. The changes in protein levels were accompanied by changes in mRNA expression of group I mGluRs and NMDARs. During the late disease phase (20–25 d.p.i.), the mRNA expression levels reached 300% of control values. In contrast, treatment with individual receptor antagonists resulted in a reduction of mRNA levels relative to untreated animals.

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Inhibition of the Group I mGluRs Reduces Acute Brain Damage and Improves Long-Term Histological Outcomes after Photothrombosis-Induced Ischaemia

ASN NEURO ◽

10.1042/an20130002 ◽

2013 ◽

Vol 5 (3) ◽

pp. AN20130002 ◽

Cited By ~ 14

Author(s):

Hailong Li ◽

Nannan Zhang ◽

Grace Sun ◽

Shinghua Ding

Keyword(s):

Brain Damage ◽

Group I ◽

Group I Mglurs

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Increased group I metabotropic glutamate receptor activity in paraventricular nucleus supports elevated sympathetic vasomotor tone in hypertension

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00195.2010 ◽

2010 ◽

Vol 299 (2) ◽

pp. R552-R561 ◽

Cited By ~ 13

Author(s):

De-Pei Li ◽

Hui-Lin Pan

Keyword(s):

Receptor Antagonist ◽

Paraventricular Nucleus ◽

Sympathetic Nerve Activity ◽

Vasomotor Tone ◽

Nerve Activity ◽

Metabotropic Glutamate ◽

Wky Rats ◽

Group I ◽

Group I Mglurs ◽

Sympathetic Vasomotor Tone

The sympathetic nerve activity is elevated in cardiovascular diseases such as hypertension. Enhanced glutamatergic inputs in the paraventricular nucleus (PVN) of the hypothalamus contribute to heightened sympathetic outflow in spontaneously hypertensive rats (SHR). We determined the role of group I metabotropic glutamate receptors (mGluR) in the PVN in the control of sympathetic vasomotor tone in hypertension. Lumbar sympathetic nerve activity (LSNA), arterial blood pressure (ABP), and heart rate (HR) were recorded in anesthetized SHR and Wistar-Kyoto (WKY) rats. Bilateral microinjection of 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), a selective mGluR5 receptor antagonist, or (S)-(+)-α-amino-4-carboxy-2-methylbenzeneacetic acid (LY367385), a selective mGluR1 receptor antagonist, into the PVN had no significant effect on LSNA and ABP in WKY rats. Strikingly, MPEP and LY367385 dose dependently decreased LSNA, ABP, and HR in SHR. The MPEP-induced decreases in LSNA and ABP were significantly greater than those inhibited by LY367385 in SHR. Furthermore, bilateral microinjection of (S)-3,5-dihydroxyphenylglycine (S-DHPG), a selective group I mGluR agonist, into the PVN caused a similar dose-dependent increase in LSNA, ABP, and HR in both groups. S-DHPG-induced responses were attenuated by MPEP or LY367385 alone and were abolished by a combination of MPEP and LY367385 in WKY rats and SHR. In addition, microinjection of the NMDA receptor antagonist attenuated the sympathoexcitatory responses induced by S-DHPG in both WKY rats and SHR. Collectively, this study provides important new evidence that the resting sympathetic vasomotor tone is maintained by tonic activation of group I mGluRs in the PVN in hypertension. Activation of NMDA receptors are involved in the sympathoexcitatory effect of group I mGluRs in the PVN.

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