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Role of Glutamate Receptors in CNS Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 12669

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Special Issue Editors

Prof. Dr. Ernesto Fedele

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Guest Editor

Pharmacology and Toxicology Unit, Department of Pharmacy, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Cembrano 4, 16148 Genoa, Italy
Interests: neuropharmacology; neurobiology; neurotransmitter release; presynaptic receptors; Alzheimer's disease; cAMP/cGMP-Abeta/Tau signalling in memory
Special Issues, Collections and Topics in MDPI journals

Dr. Tiziana Bonifacino

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Guest Editor

Pharmacology and Toxicology Unit, Department of Pharmacy, School of Medical and Pharmaceutical Sciences, University of Genoa, 16132 Genoa, Italy
Interests: neuropharmacology; neurobiology; neurotransmitter release; glutamate receptors; amyotrohic latera sclerosis; post-traumatic stress disorder; pharmacological treatments

Special Issue Information

Dear Colleagues,

Glutamate is a fundamental excitatory neurotransmitter in the central nervous system (CNS), and the role of glutamatergic neurotransmission has been established through a long research history, playing key roles in memory, neuronal development, and synaptic plasticity. Glutamate receptors are subdivided into two classes: ionotropic receptors, which act as ion channels (AMPA, NMDA and kainite receptors), and metabotropic receptors (mGluRs), which belong to the GPCRs that modulate cascades of intracellular second messengers. Since receptor dysregulation is involved in a variety of neurological and psychiatric disorders, such as mood disorders, Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, multiple sclerosis, and chronic pain, preclinical translational studies are actively required to determine the precise role of glutamate receptors in different pathological scenarios.

This Special Issue aims to collect a selection of research papers and reviews that focus on the role of glutamate receptors in CNS diseases and that will help the scientific community to better understand the underlying molecular pathomechanisms and identify new potential pharmacological targets.

Prof. Ernesto Fedele
Dr. Tiziana Bonifacino
Guest Editors

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Keywords

glutamate receptors
CNS diseases
neurodegeneration
excitotoxicity
psychiatric disorders
neurological diseases
mood disorders
amyotrophic lateral sclerosis
Parkinson’s disease
Alzheimer’s disease
multiple sclerosis
chronic pain

Published Papers (6 papers)

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Research

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15 pages, 2710 KiB

Open AccessArticle

Functional and Molecular Changes in the Prefrontal Cortex of the Chronic Mild Stress Rat Model of Depression and Modulation by Acute Ketamine

by Jessica Mingardi, Elona Ndoj, Tiziana Bonifacino, Paulina Misztak, Matteo Bertoli, Luca La Via, Carola Torazza, Isabella Russo, Marco Milanese, Giambattista Bonanno, Maurizio Popoli, Alessandro Barbon and Laura Musazzi

Int. J. Mol. Sci. 2023, 24(13), 10814; https://doi.org/10.3390/ijms241310814 - 28 Jun 2023

Cited by 1 | Viewed by 1301

Abstract

Stress is a primary risk factor in the onset of neuropsychiatric disorders, including major depressive disorder (MDD). We have previously used the chronic mild stress (CMS) model of depression in male rats to show that CMS induces morphological, functional, and molecular changes in the hippocampus of vulnerable animals, the majority of which were recovered using acute subanesthetic ketamine in just 24 h. Here, we focused our attention on the medial prefrontal cortex (mPFC), a brain area regulating emotional and cognitive functions, and asked whether vulnerability/resilience to CMS and ketamine antidepressant effects were associated with molecular and functional changes in the mPFC of rats. We found that most alterations induced by CMS in the mPFC were selectively observed in stress-vulnerable animals and were rescued by acute subanesthetic ketamine, while others were found only in resilient animals or were induced by ketamine treatment. Importantly, only a few of these modifications were also previously demonstrated in the hippocampus, while most are specific to mPFC. Overall, our results suggest that acute antidepressant ketamine rescues brain-area-specific glutamatergic changes induced by chronic stress. Full article

(This article belongs to the Special Issue Role of Glutamate Receptors in CNS Diseases)

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14 pages, 2364 KiB

Open AccessArticle

Pharmacological Modulation of Excitotoxicity through the Combined Use of NMDA Receptor Inhibition and Group III mGlu Activation Reduces TMT-Induced Neurodegeneration in the Rat Hippocampus

by Ekaterina V. Pershina, Irina Yu. Chernomorets, Dmitry A. Fedorov and Vladimir I. Arkhipov

Int. J. Mol. Sci. 2023, 24(9), 8249; https://doi.org/10.3390/ijms24098249 - 4 May 2023

Cited by 1 | Viewed by 1330

Abstract

We studied the neuroprotective properties of the non-competitive NMDA receptor antagonist memantine, in combination with a positive allosteric modulator of metabotropic glutamate receptors of Group III, VU 0422288. The treatment was started 48 h after the injection of neurotoxic agent trimethyltin (TMT) at 7.5 mg/kg. Three weeks after TMT injection, functional and morphological changes in a rat hippocampus were evaluated, including the expression level of genes characterizing glutamate transmission and neuroinflammation, animal behavior, and hippocampal cell morphology. Significant neuronal cell death occurred in the CA3 and CA4 regions, and to a lesser extent, in the CA1 and CA2 regions. The death of neurons in the CA1 field was significantly reduced in animals with a combined use of memantine and VU 0422288. In the hippocampus of these animals, the level of expression of genes characterizing glutamatergic synaptic transmission (Grin2b, Gria1, EAAT2) did not differ from the level in control animals, as well as the expression of genes characterizing neuroinflammation (IL1b, TGF beta 1, Aif1, and GFAP). However, the expression of genes characterizing neuroinflammation was markedly increased in the hippocampus of animals treated with memantine or VU 0422288 alone after TMT. The results of immunohistochemical studies confirmed a significant activation of microglia in the hippocampus three weeks after TMT injection. In contrast to the hilus, microglia in the CA1 region had an increase in rod-like cells. Moreover, in the CA1 field of the hippocampus of the animals of the MEM + VU group, the amount of such microglia was close to the control. Thus, the short-term modulation of glutamatergic synaptic transmission by memantine and subsequent activation of Group III mGluR significantly affected the dynamics of neurodegeneration in the hippocampus. Full article

(This article belongs to the Special Issue Role of Glutamate Receptors in CNS Diseases)

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11 pages, 1672 KiB

Open AccessArticle

Calcium-Dependent Interplay of Lithium and Tricyclic Antidepressants, Amitriptyline and Desipramine, on N-methyl-D-aspartate Receptors

by Sergei I. Boikov, Dmitry A. Sibarov, Yulia D. Stepanenko, Tatiana V. Karelina and Sergei M. Antonov

Int. J. Mol. Sci. 2022, 23(24), 16177; https://doi.org/10.3390/ijms232416177 - 19 Dec 2022

Cited by 2 | Viewed by 1391

Abstract

The facilitated activity of N-methyl-D-aspartate receptors (NMDARs) in the central and peripheral nervous systems promotes neuropathic pain. Amitriptyline (ATL) and desipramine (DES) are tricyclic antidepressants (TCAs) whose anti-NMDAR properties contribute to their analgetic effects. At therapeutic concentrations <1 µM, these medicines inhibit NMDARs by enhancing their calcium-dependent desensitization (CDD). Li⁺, which suppresses the sodium–calcium exchanger (NCX) and enhances NMDAR CDD, also exhibits analgesia. Here, the effects of different [Li⁺]s on TCA inhibition of currents through native NMDARs in rat cortical neurons recorded by the patch-clamp technique were investigated. We demonstrated that the therapeutic [Li⁺]s of 0.5–1 mM cause an increase in ATL and DES IC₅₀s of ~10 folds and ~4 folds, respectively, for the Ca²⁺-dependent NMDAR inhibition. The Ca²⁺-resistant component of NMDAR inhibition by TCAs, the open-channel block, was not affected by Li⁺. In agreement, clomipramine providing exclusively the NMDAR open-channel block is not sensitive to Li⁺. This Ca²⁺-dependent interplay between Li⁺, ATL, and DES could be determined by their competition for the same molecular target. Thus, submillimolar [Li⁺]s may weaken ATL and DES effects during combined therapy. The data suggest that Li⁺, ATL, and DES can enhance NMDAR CDD through NCX inhibition. This ability implies a drug–drug or ion–drug interaction when these medicines are used together therapeutically. Full article

(This article belongs to the Special Issue Role of Glutamate Receptors in CNS Diseases)

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Review

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37 pages, 5927 KiB

Open AccessReview

The Key Role of Astrocytes in Amyotrophic Lateral Sclerosis and Their Commitment to Glutamate Excitotoxicity

by Francesca Provenzano, Carola Torazza, Tiziana Bonifacino, Giambattista Bonanno and Marco Milanese

Int. J. Mol. Sci. 2023, 24(20), 15430; https://doi.org/10.3390/ijms242015430 - 21 Oct 2023

Cited by 1 | Viewed by 2043

Abstract

In the last two decades, there has been increasing evidence supporting non-neuronal cells as active contributors to neurodegenerative disorders. Among glial cells, astrocytes play a pivotal role in driving amyotrophic lateral sclerosis (ALS) progression, leading the scientific community to focus on the “astrocytic signature” in ALS. Here, we summarized the main pathological mechanisms characterizing astrocyte contribution to MN damage and ALS progression, such as neuroinflammation, mitochondrial dysfunction, oxidative stress, energy metabolism impairment, miRNAs and extracellular vesicles contribution, autophagy dysfunction, protein misfolding, and altered neurotrophic factor release. Since glutamate excitotoxicity is one of the most relevant ALS features, we focused on the specific contribution of ALS astrocytes in this aspect, highlighting the known or potential molecular mechanisms by which astrocytes participate in increasing the extracellular glutamate level in ALS and, conversely, undergo the toxic effect of the excessive glutamate. In this scenario, astrocytes can behave as “producers” and “targets” of the high extracellular glutamate levels, going through changes that can affect themselves and, in turn, the neuronal and non-neuronal surrounding cells, thus actively impacting the ALS course. Moreover, this review aims to point out knowledge gaps that deserve further investigation. Full article

(This article belongs to the Special Issue Role of Glutamate Receptors in CNS Diseases)

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33 pages, 3764 KiB

Open AccessReview

Kainate Receptor Antagonists: Recent Advances and Therapeutic Perspective

by Paulina Chałupnik and Ewa Szymańska

Int. J. Mol. Sci. 2023, 24(3), 1908; https://doi.org/10.3390/ijms24031908 - 18 Jan 2023

Cited by 6 | Viewed by 3902

Abstract

Since the 1990s, ionotropic glutamate receptors have served as an outstanding target for drug discovery research aimed at the discovery of new neurotherapeutic agents. With the recent approval of perampanel, the first marketed non-competitive antagonist of AMPA receptors, particular interest has been directed toward ‘non-NMDA’ (AMPA and kainate) receptor inhibitors. Although the role of AMPA receptors in the development of neurological or psychiatric disorders has been well recognized and characterized, progress in understanding the function of kainate receptors (KARs) has been hampered, mainly due to the lack of specific and selective pharmacological tools. The latest findings in the biology of KA receptors indicate that they are involved in neurophysiological activity and play an important role in both health and disease, including conditions such as anxiety, schizophrenia, epilepsy, neuropathic pain, and migraine. Therefore, we reviewed recent advances in the field of competitive and non-competitive kainate receptor antagonists and their potential therapeutic applications. Due to the high level of structural divergence among the compounds described here, we decided to divide them into seven groups according to their overall structure, presenting a total of 72 active compounds. Full article

(This article belongs to the Special Issue Role of Glutamate Receptors in CNS Diseases)

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16 pages, 2024 KiB

Open AccessReview

Focusing on the Emerging Role of Kainate Receptors in the Dorsal Cochlear Nucleus (DCN) and Cerebellum

by Qin-Wei Wu and Zheng-Quan Tang

Int. J. Mol. Sci. 2023, 24(2), 1718; https://doi.org/10.3390/ijms24021718 - 15 Jan 2023

Cited by 3 | Viewed by 2067

Abstract

Mammals have a dorsal cochlear nucleus (DCN), which is thought to be a cerebellum-like structure with similar features in terms of structure and microcircuitry to the cerebellum. Both the DCN and cerebellum perform their functions depending on synaptic and neuronal networks mediated by various glutamate receptors. Kainate receptors (KARs) are one class of the glutamate receptor family and are strongly expressed in the hippocampus, the cerebellum, and cerebellum-like structures. The cellular distribution and the potential role of KARs in the hippocampus have been extensively investigated. However, the cellular distribution and the potential role of KARs in cerebellum-like structures, including the DCN and cerebellum, are poorly understood. In this review, we summarize the similarity between the DCN and cerebellum at the levels of structure, circuitry, and cell type as well as the investigations referring to the expression patterns of KARs in the DCN and cerebellum according to previous studies. Recent studies on the role of KARs have shown that KARs mediate a bidirectional modulatory effect at parallel fiber (PF)–Purkinje cell (PC) synapses in the cerebellum, implying insights into their roles in cerebellum-like structures, including the DCN, that remain to be explored in the coming years. Full article

(This article belongs to the Special Issue Role of Glutamate Receptors in CNS Diseases)

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