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Life
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Glutamate Receptors
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Glutamate Receptors

A special issue of Life (ISSN 2075-1729). This special issue belongs to the section "Pharmaceutical Science".

Deadline for manuscript submissions: closed (26 November 2021) | Viewed by 17447

Special Issue Editors

Prof. Dr. Jolanta H. Kotlińska

E-Mail Website
Guest Editor
Department of Pharmacology and Pharmacodynamics, Medical University, Chodzki 4A, 20-093 Lublin, Poland
Interests: pharmacology; central nervous system; addiction; pain; learning and memory; anxiety; depression; glutamate receptors
Special Issues, Collections and Topics in MDPI journals
Dr. Marta Marszalek-Grabska

E-Mail Website
Guest Editor
Department of Experimental and Clinical Pharmacology, Medical University of Lublin, 20-059 Lublin, Poland
Interests: pharmacology; central nervous system; memory; addiction; glutamate; metabotropic glutamate receptors

Special Issue Information

Dear Collogues,

Glutamate, the main excitatory neurotransmitter in the mammalian central nervous system (CNS), is responsible for many neurobiological functions (memory, neuronal development, and synaptic plasticity), and also a variety of pathologic conditions (stroke and various neurodegenerative disorders) when it is excessively released.

Glutamate receptors fall into one of two categories: ligand-gated ion channels (i.e., ionotropic glutamate receptors, or iGluRs) which mediate fast excitatory neurotransmission, and G-protein coupled receptors (i.e., metabotropic glutamate receptors, or mGluRs) which mediate slower, modulatory neurotransmission. In light of the unwanted side effects induced by iGluR antagonists (memory loss, disorientation, and symptoms of psychosis) significant efforts have been undertaken to pharmacologically manipulate glutamate transmission with selective mGluRs ligands. These have been shown to be of potential benefit in the treatment of addiction and other disorders of the CNS, including chronic pain, Parkinson’s disease, depression, anxiety, epilepsy, and neurodegeneration.

So far, eight different mGluR subtypes have been cloned and characterized that are located either in the perisynaptic annulus or on presynaptic terminals and have diverse neuroanatomical distributions and unique pharmacological and intracellular signaling properties. The mGluRs can be divided into Group I (mGlu1 and mGlu5), Group II (mGlu2 and mGlu3), and Group III (mGlu4, mGlu6, mGlu7, and mGlu8). Group I mGluRs, particularly mGluR5, are positively coupled to N-methyl-D-aspartate receptor (NMDAR) function and the Homer family of proteins. Group I mGluRs are rarely found presynaptically. Presynaptically localized Group II and Group III mGluRs, notably mGluR2 and mGluR3, are the classic inhibitory autoreceptors that suppress excess glutamate release from the presynaptic terminal. In recent years, positive allosteric modulators of mGluRs have also been synthesized. These compounds are an exciting advance for the development of novel therapeutic agents for increasing the activity of mGluR subtypes.

All authors are cordially invited to contribute original research papers or reviews that target mGluRs to this Special Issue of Life.

Prof. Dr. Jolanta H. Kotlińska
Dr. Marta Marszalek-Grabska
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Life is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • central nervous system
  • metabotropic glutamate receptors
  • allosteric modulators
  • synaptic plasticity
  • memory
  • addiction
  • anxiety
  • neurodegenerative disorders
  • pain
  • depression
  • epilepsy

Published Papers (6 papers)

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Research

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10 pages, 1246 KiB  
Article
N-Methyl-D-Aspartate (NMDA) Receptors in the Prelimbic Cortex Are Required for Short- and Long-Term Memory Formation in Trace Fear Conditioning
by Eui-Ho Park, Nam-Soo Kim, Yeon-Kyung Lee and June-Seek Choi
Life 2022, 12(5), 672; https://doi.org/10.3390/life12050672 - 01 May 2022
Cited by 2 | Viewed by 2556
Abstract
Accumulating evidence suggests that the medial prefrontal cortex (mPFC) has been implicated in the acquisition of fear memory during trace fear conditioning in which a conditional stimulus (CS) is paired with an aversive unconditional stimulus (UCS) separated by a temporal gap (trace interval, [...] Read more.
Accumulating evidence suggests that the medial prefrontal cortex (mPFC) has been implicated in the acquisition of fear memory during trace fear conditioning in which a conditional stimulus (CS) is paired with an aversive unconditional stimulus (UCS) separated by a temporal gap (trace interval, TI). However, little is known about the role of the prefrontal cortex for short- and long-term trace fear memory formation. Thus, we investigated how the prelimbic (PL) subregion within mPFC in rats contributes to short- and long-term trace fear memory formation using electrolytic lesions and d,l,-2-amino-5-phosphonovaleric acid (APV), an N-methyl-D-aspartate receptor (NMDAR) antagonist infusions into PL. In experiment 1, pre-conditioning lesions of PL impaired freezing to the CS as well as TI during the acquisition and retrieval sessions, indicating that PL is critically involved in trace fear memory formation. In experiment 2, temporary blockade of NMDA receptors in PL impaired the acquisition, but not the expression of short- and long-term trace fear memory. In addition, the inactivation of NMDAR in PL had little effect on locomotor activity, pre-pulse inhibition (PPI), or shock sensitivity. Taken together, these results suggest that NMDA receptor-mediated neurotransmission in PL is required for the acquisition of trace fear memory. Full article
(This article belongs to the Special Issue Glutamate Receptors)
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8 pages, 457 KiB  
Article
Glutamate as a Stressoric Factor for the Ex Vivo Release of Catecholamines from the Rabbit Medial Prefrontal Cortex (mPFC)
by Bogdan Feliks Kania, Danuta Wrońska, Izabela Szpręgiel and Urszula Bracha
Life 2021, 11(12), 1386; https://doi.org/10.3390/life11121386 - 11 Dec 2021
Viewed by 2029
Abstract
One of the major roles of glutamic acid (Glu) is to serve as an excitatory neurotransmitter within the central nervous system (CNS). This amino acid influences the activity of several brain areas, including the thalamus, brainstem, spinal cord, basal ganglia, and pons. Catecholamines [...] Read more.
One of the major roles of glutamic acid (Glu) is to serve as an excitatory neurotransmitter within the central nervous system (CNS). This amino acid influences the activity of several brain areas, including the thalamus, brainstem, spinal cord, basal ganglia, and pons. Catecholamines (CAs) are synthesized in the brain and adrenal medulla and by some sympathetic nerve fibers. CAs, including dopamine (DA), norepinephrine (NE), and epinephrine (E), are the principal neurotransmitters that mediate a variety of CNS functions, such as motor control, cognition, emotion, memory processing, pain, stress, and endocrine modulation. This study aims to investigate the effects of the application of various Glu concentrates (5, 50, and 200 µM) on CAs release from rabbit medial prefrontal cortex (mPFC) slices and compare any resulting correlations with CAs released from the hypothalamus during 90 min of incubation. Medial prefrontal cortex samples were dissected from decapitated, twelve-week-old female rabbits. The results demonstrated that Glu differentially influences the direct release of CAs from the mPFC and the indirect release of CAs from the hypothalamus. When under stress, the hypothalamus, a central brain structure of the HPA axis, induces and adapts such processes. Generally, there was an inhibitory effect of Glu on CAs release from mPFC slices. Our findings show that the effect arises from Glu’s action on higher-order motivational structures, which may indicate its contribution to the stress response by modulating the amount of CAs released. Full article
(This article belongs to the Special Issue Glutamate Receptors)
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16 pages, 2406 KiB  
Article
Properties of GABAergic Neurons Containing Calcium-Permeable Kainate and AMPA-Receptors
by Valery Petrovich Zinchenko, Artem Mikhailovich Kosenkov, Sergei Gennadevich Gaidin, Alexander Igorevich Sergeev, Ludmila Petrovna Dolgacheva and Sultan Tuleukhanovich Tuleukhanov
Life 2021, 11(12), 1309; https://doi.org/10.3390/life11121309 - 27 Nov 2021
Cited by 6 | Viewed by 2194
Abstract
Calcium-permeable kainate and AMPA receptors (CP-KARs and CP-AMPARs), as well as NMDARs, play a pivotal role in plasticity and in regulating neurotransmitter release. Here we visualized in the mature hippocampal neuroglial cultures the neurons expressing CP-AMPARs and CP-KARs. These neurons were visualized by [...] Read more.
Calcium-permeable kainate and AMPA receptors (CP-KARs and CP-AMPARs), as well as NMDARs, play a pivotal role in plasticity and in regulating neurotransmitter release. Here we visualized in the mature hippocampal neuroglial cultures the neurons expressing CP-AMPARs and CP-KARs. These neurons were visualized by a characteristic fast sustained [Ca2+]i increase in response to the agonist of these receptors, domoic acid (DoA), and a selective agonist of GluK1-containing KARs, ATPA. Neurons from both subpopulations are GABAergic. The subpopulation of neurons expressing CP-AMPARs includes a larger percentage of calbindin-positive neurons (39.4 ± 6.0%) than the subpopulation of neurons expressing CP-KARs (14.2 ± 7.5% of CB+ neurons). In addition, we have shown for the first time that NH4Cl-induced depolarization faster induces an [Ca2+]i elevation in GABAergic neurons expressing CP-KARs and CP-AMPARs than in most glutamatergic neurons. CP-AMPARs antagonist, NASPM, increased the amplitude of the DoA-induced Ca2+ response in GABAergic neurons expressing CP-KARs, indicating that neurons expressing CP-AMPARs innervate GABAergic neurons expressing CP-KARs. We assume that CP-KARs in inhibitory neurons are involved in the mechanism of outstripping GABA release upon hyperexcitation. Full article
(This article belongs to the Special Issue Glutamate Receptors)
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13 pages, 1009 KiB  
Article
Loss of Group II Metabotropic Glutamate Receptor Signaling Exacerbates Hypertension in Spontaneously Hypertensive Rats
by Julia Chu-Ning Hsu, Shinichi Sekizawa, Ryota Tochinai and Masayoshi Kuwahara
Life 2021, 11(7), 720; https://doi.org/10.3390/life11070720 - 20 Jul 2021
Cited by 1 | Viewed by 2466
Abstract
High blood pressure is a major risk factor of cerebro-cardiovascular outcomes. Blood pressure is partly regulated by the autonomic nervous system and its reflex functions; therefore, we hypothesized that pharmacological intervention in the brainstem that can regulate blood pressure could be a novel [...] Read more.
High blood pressure is a major risk factor of cerebro-cardiovascular outcomes. Blood pressure is partly regulated by the autonomic nervous system and its reflex functions; therefore, we hypothesized that pharmacological intervention in the brainstem that can regulate blood pressure could be a novel therapeutic strategy to control hypertension. We infused a group II metabotropic glutamate receptor (mGluR) antagonist (LY341495, 0.40 μg/day), using a mini-osmotic pump, into the dorsal medulla oblongata in young spontaneously hypertensive rats (SHRs), as this area is adjacent to the nucleus tractus solitarius (NTS), of which the neurons are involved in baroreflex pathways with glutamatergic transmission. Blood pressure was recorded for conscious rats with the tail cuff method. A 6-week antagonist treatment from 6 to 12 weeks of age slightly but significantly increased systolic blood pressure by >30 mmHg, compared to that in SHRs without treatment. Moreover, the effect continued even 3 weeks after the treatment ended, and concurred with an increase in blood catecholamine concentration. However, heart rate variability analysis revealed that LY341495 treatment had little effect on autonomic activity. Meanwhile, mRNA expression level of mGluR subtype 2, but not subtype 3 in the brainstem was significantly enhanced by the antagonist treatment in SHRs, possibly compensating the lack of mGluR signaling. In conclusion, mGluR2 signaling in the dorsal brainstem is crucial for preventing the worsening of hypertension over a relatively long period in SHRs, through a mechanism of catecholamine secretion. This may be a specific drug target for hypertension therapy. Full article
(This article belongs to the Special Issue Glutamate Receptors)
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19 pages, 1812 KiB  
Article
Functional Analysis of Brain Imaging Suggests Changes in the Availability of mGluR5 and Altered Connectivity in the Cerebral Cortex of Long-Term Abstaining Males with Alcohol Dependence: A Preliminary Study
by Yo-Han Joo, Jeong-Hee Kim, Hang-Keun Kim, Young-Don Son, Paul Cumming and Jong-Hoon Kim
Life 2021, 11(6), 506; https://doi.org/10.3390/life11060506 - 30 May 2021
Cited by 3 | Viewed by 2731
Abstract
Direct in vivo evidence of altered metabotropic glutamate receptor-5 (mGluR5) availability in alcohol-related disorders is lacking. We performed [11C]ABP688 positron emission tomography (PET) and resting-state functional magnetic resonance imaging (rs-fMRI) in prolonged abstinent subjects with alcohol dependence to examine alterations of [...] Read more.
Direct in vivo evidence of altered metabotropic glutamate receptor-5 (mGluR5) availability in alcohol-related disorders is lacking. We performed [11C]ABP688 positron emission tomography (PET) and resting-state functional magnetic resonance imaging (rs-fMRI) in prolonged abstinent subjects with alcohol dependence to examine alterations of mGluR5 availability, and to investigate their functional significance relating to neural systems-level changes. Twelve prolonged abstinent male subjects with alcohol dependence (median abstinence duration: six months) and ten healthy male controls underwent [11C]ABP688 PET imaging and 3-Tesla MRI. For mGluR5 availability, binding potential (BPND) was calculated using the simplified reference tissue model with cerebellar gray matter as the reference region. The initial region-of-interest (ROI)-based analysis yielded no significant group differences in mGluR5 availability. The voxel-based analysis revealed significantly lower [11C]ABP688 BPND in the middle temporal and inferior parietal cortices, and higher BPND in the superior temporal cortex in the alcohol dependence group compared with controls. Functional connectivity analysis of the rs-fMRI data employed seed regions identified from the quantitative [11C]ABP688 PET analysis, which revealed significantly altered functional connectivity from the inferior parietal cortex seed to the occipital pole and dorsal visual cortex in the alcohol dependence group compared with the control group. To our knowledge, this is the first report on the combined analysis of mGluR5 PET imaging and rs-fMRI in subjects with alcohol dependence. These preliminary results suggest the possibility of region-specific alterations of mGluR5 availability in vivo and related functional connectivity perturbations in prolonged abstinent subjects. Full article
(This article belongs to the Special Issue Glutamate Receptors)
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Review

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16 pages, 1383 KiB  
Review
Brain Insulin Resistance: Focus on Insulin Receptor-Mitochondria Interactions
by Igor Pomytkin and Vsevolod Pinelis
Life 2021, 11(3), 262; https://doi.org/10.3390/life11030262 - 22 Mar 2021
Cited by 17 | Viewed by 4130
Abstract
Current hypotheses implicate insulin resistance of the brain as a pathogenic factor in the development of Alzheimer’s disease and other dementias, Parkinson’s disease, type 2 diabetes, obesity, major depression, and traumatic brain injury. A variety of genetic, developmental, and metabolic abnormalities that lead [...] Read more.
Current hypotheses implicate insulin resistance of the brain as a pathogenic factor in the development of Alzheimer’s disease and other dementias, Parkinson’s disease, type 2 diabetes, obesity, major depression, and traumatic brain injury. A variety of genetic, developmental, and metabolic abnormalities that lead to disturbances in the insulin receptor signal transduction may underlie insulin resistance. Insulin receptor substrate proteins are generally considered to be the node in the insulin signaling system that is critically involved in the development of insulin insensitivity during metabolic stress, hyperinsulinemia, and inflammation. Emerging evidence suggests that lower activation of the insulin receptor (IR) is another common, while less discussed, mechanism of insulin resistance in the brain. This review aims to discuss causes behind the diminished activation of IR in neurons, with a focus on the functional relationship between mitochondria and IR during early insulin signaling and the related roles of oxidative stress, mitochondrial hypometabolism, and glutamate excitotoxicity in the development of IR insensitivity to insulin. Full article
(This article belongs to the Special Issue Glutamate Receptors)
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