Glutamate and Glutamate Receptors in Health and Diseases

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (30 April 2024) | Viewed by 11689

Special Issue Editors


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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
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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 Colleagues,

The history of glutamate as a neurotransmitter began with T. Hayashi in 1952, when he reported that glutamate injections into dog cerebral ventricles induced seizures.Since then, it has become clear that glutamate is a major excitatory neurotransmitter in the mammalian central nervous system (CNS), and is essential for proper neuronal development, synaptic plasticity and learning and memory. It acts through the activation of glutamate receptors that are subdivided into the following two classes: ionotropic receptors, which act as ion channels (AMPA, NMDA and kainate receptors), and metabotropic receptors (mGluRs), which belong to the GPCRs that modulate cascades of intracellular second messengers. Disturbances in glutamatergic function have been implicated in the pathophysiology of several neuropsychiatric disorders, including schizophrenia, drug abuse and addiction, autism, and depression, as well as in neurodegenerative diseases that were until recently poorly understood.

This Special Issue “Glutamate and Glutamate Receptors in Health and Diseases” aims to collect research papers and reviews that focus on the role of glutamate or its receptors in CNS diseases. The intent is to provide novel mechanistic insights into the function of glutamate and glutamate receptors and their translational value for human diseases. We hope that this research can identify new potential pharmacological targets for therapy.

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

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Keywords

  • glutamate receptors
  • addiction
  • pain
  • learning and memory
  • anxiety
  • depression
  • autism
  • neurodegeneration

Published Papers (6 papers)

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Research

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17 pages, 1085 KiB  
Article
Neonatal Maternal Separation Induces Sexual Dimorphism in Brain Development: The Influence on Amino Acid Levels and Cognitive Disorders
by Jolanta H. Kotlinska, Pawel Grochecki, Agnieszka Michalak, Anna Pankowska, Katarzyna Kochalska, Piotr Suder, Joanna Ner-Kluza, Dariusz Matosiuk and Marta Marszalek-Grabska
Biomolecules 2023, 13(10), 1449; https://doi.org/10.3390/biom13101449 - 26 Sep 2023
Cited by 3 | Viewed by 1484
Abstract
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 [...] Read more.
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
(This article belongs to the Special Issue Glutamate and Glutamate Receptors in Health and Diseases)
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14 pages, 2682 KiB  
Article
Esketamine Inhibits Cocaine-Seeking Behaviour Subsequent to Various Abstinence Conditions in Rats
by Karolina Wydra, Kacper Witek, Agata Suder and Małgorzata Filip
Biomolecules 2023, 13(9), 1411; https://doi.org/10.3390/biom13091411 - 19 Sep 2023
Cited by 1 | Viewed by 1353
Abstract
Background: Cocaine use disorder (CUD) is a relapsing brain disease caused by a chronic drug intake that involves neural mechanisms and psychological processes, including depression. Preclinical and clinical studies have demonstrated the promise of pharmacological drugs in controlling the reinstatement of cocaine by [...] Read more.
Background: Cocaine use disorder (CUD) is a relapsing brain disease caused by a chronic drug intake that involves neural mechanisms and psychological processes, including depression. Preclinical and clinical studies have demonstrated the promise of pharmacological drugs in controlling the reinstatement of cocaine by targeting the N-methyl-D-aspartate (NMDA) receptor. Recent evidence has revealed that esketamine, a (S) enantiomer of ketamine, shows a high affinity to NMDA receptors and has been used in clinical trials to treat moderate-to-severe depression. Methods: In the present paper, we investigated the effects of esketamine in regulating cocaine-seeking behaviour induced through the use of cocaine (10 mg/kg) or the cocaine-associated conditioned cue after a short (10 days)-lasting period of drug abstinence with extinction training, home cage or enrichment environment conditions in male rats. Furthermore, we investigated the acute effects of esketamine on locomotor activity in drug-naïve animals. Results: Esketamine (2.5–10 mg/kg) administered peripherally attenuated the reinstatement induced with cocaine priming or the drug-associated conditioned cue after different conditions of abstinence. Conclusions: These results seem to support esketamine as a candidate for the pharmacological management of cocaine-seeking and relapse prevention; however, further preclinical and clinical research is needed to better clarify esketamine’s actions in CUD. Full article
(This article belongs to the Special Issue Glutamate and Glutamate Receptors in Health and Diseases)
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18 pages, 2548 KiB  
Article
Activation of Metabotropic Glutamate Receptor (mGlu2) and Muscarinic Receptors (M1, M4, and M5), Alone or in Combination, and Its Impact on the Acquisition and Retention of Learning in the Morris Water Maze, NMDA Expression and cGMP Synthesis
by Joanna M. Wierońska, Paulina Cieślik, Grzegorz Burnat and Leszek Kalinowski
Biomolecules 2023, 13(7), 1064; https://doi.org/10.3390/biom13071064 - 30 Jun 2023
Cited by 4 | Viewed by 1661
Abstract
The Morris water maze (MWM) is regarded as one of the most popular tests for detecting spatial memory in rodents. Long-term potentiation and cGMP synthesis seem to be among the crucial factors involved in this type of learning. Muscarinic (M1, M [...] Read more.
The Morris water maze (MWM) is regarded as one of the most popular tests for detecting spatial memory in rodents. Long-term potentiation and cGMP synthesis seem to be among the crucial factors involved in this type of learning. Muscarinic (M1, M4, and M5 receptors) and metabotropic glutamate (mGlu) receptors are important targets in the search for antipsychotic drugs with the potency to treat cognitive disabilities associated with the disorder. Here, we show that muscarinic receptor activators (VU0357017, VU0152100, and VU0238429) and an mGlu2 receptor activator, LY487379, dose-dependently prevented the development of cognitive disorders as a result of MK-801 administration in the MWM. The dose-ranges of the compounds were as follows: VU0357017, 0.25, 0.5, and 1 mg/kg; VU0152100, 0.05, 0.25, and 1 mg/kg; VU0238429, 1, 5, and 20 mg/kg; and LY487379, 0.5, 3, and 5 mg/kg. The co-administration of LY487379 with each of the individual muscarinic receptor ligands showed no synergistic effect, which contradicts the results obtained earlier in the novel object recognition (NOR) test. MWM learning resulted in increased cGMP synthesis, both in the cortex and hippocampi, when compared to that in intact animals, which was prevented by MK-801 administration. The investigated compounds at the highest doses reversed this MK-801-induced effect. Neither the procedure nor the treatment resulted in changes in GluN2B-NMDA expression. Full article
(This article belongs to the Special Issue Glutamate and Glutamate Receptors in Health and Diseases)
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19 pages, 3251 KiB  
Article
Enhanced L-β-Aminoisobutyric Acid Is Involved in the Pathophysiology of Effectiveness for Treatment-Resistant Schizophrenia and Adverse Reactions of Clozapine
by Kouji Fukuyama, Eishi Motomura and Motohiro Okada
Biomolecules 2023, 13(5), 862; https://doi.org/10.3390/biom13050862 - 19 May 2023
Cited by 2 | Viewed by 1868
Abstract
Clozapine is an effective antipsychotic for the treatment of antipsychotic-resistant schizophrenia; however, specific types of A/B adverse effects and clozapine-discontinuation syndromes are also well known. To date, both the critical mechanisms of clinical actions (effective for antipsychotic-resistant schizophrenia) and the adverse effects of [...] Read more.
Clozapine is an effective antipsychotic for the treatment of antipsychotic-resistant schizophrenia; however, specific types of A/B adverse effects and clozapine-discontinuation syndromes are also well known. To date, both the critical mechanisms of clinical actions (effective for antipsychotic-resistant schizophrenia) and the adverse effects of clozapine remain to be elucidated. Recently, we demonstrated that clozapine increased the synthesis of L-β-aminoisobutyric acid (L-BAIBA) in the hypothalamus. L-BAIBA is an activator of the adenosine monophosphate-activated protein kinase (AMPK), glycine receptor, GABAA receptor, and GABAB receptor (GABAB-R). These targets of L-BAIBA overlap as potential targets other than the monoamine receptors of clozapine. However, the direct binding of clozapine to these aminoacidic transmitter/modulator receptors remains to be clarified. Therefore, to explore the contribution of increased L-BAIBA on the clinical action of clozapine, this study determined the effects of clozapine and L-BAIBA on tripartite synaptic transmission, including GABAB-R and the group-III metabotropic glutamate receptor (III-mGluR) using cultured astrocytes, as well as on the thalamocortical hyper-glutamatergic transmission induced by impaired glutamate/NMDA receptors using microdialysis. Clozapine increased astroglial L-BAIBA synthesis in time/concentration-dependent manners. Increased L-BAIBA synthesis was observed until 3 days after clozapine discontinuation. Clozapine did not directly bind III-mGluR or GABAB-R, whereas L-BAIBA activated these receptors in the astrocytes. Local administration of MK801 into the reticular thalamic nucleus (RTN) increased L-glutamate release in the medial frontal cortex (mPFC) (MK801-evoked L-glutamate release). Local administration of L-BAIBA into the mPFC suppressed MK801-evoked L-glutamate release. These actions of L-BAIBA were inhibited by antagonists of III-mGluR and GABAB-R, similar to clozapine. These in vitro and in vivo analyses suggest that increased frontal L-BAIBA signaling likely plays an important role in the pharmacological actions of clozapine, such as improving the effectiveness of treating treatment-resistant schizophrenia and several clozapine discontinuation syndromes via the activation of III-mGluR and GABAB-R in the mPFC. Full article
(This article belongs to the Special Issue Glutamate and Glutamate Receptors in Health and Diseases)
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20 pages, 4132 KiB  
Article
Tubulin Polyglutamylation by TTLL1 and TTLL7 Regulate Glutamate Concentration in the Mice Brain
by Yashuang Ping, Kenji Ohata, Kenji Kikushima, Takumi Sakamoto, Ariful Islam, Lili Xu, Hengsen Zhang, Bin Chen, Jing Yan, Fumihiro Eto, Chiho Nakane, Keizo Takao, Tsuyoshi Miyakawa, Katsuya Kabashima, Miho Watanabe, Tomoaki Kahyo, Ikuko Yao, Atsuo Fukuda, Koji Ikegami, Yoshiyuki Konishi and Mitsutoshi Setouadd Show full author list remove Hide full author list
Biomolecules 2023, 13(5), 784; https://doi.org/10.3390/biom13050784 - 1 May 2023
Viewed by 2650
Abstract
As an important neurotransmitter, glutamate acts in over 90% of excitatory synapses in the human brain. Its metabolic pathway is complicated, and the glutamate pool in neurons has not been fully elucidated. Tubulin polyglutamylation in the brain is mainly mediated by two tubulin [...] Read more.
As an important neurotransmitter, glutamate acts in over 90% of excitatory synapses in the human brain. Its metabolic pathway is complicated, and the glutamate pool in neurons has not been fully elucidated. Tubulin polyglutamylation in the brain is mainly mediated by two tubulin tyrosine ligase-like (TTLL) proteins, TTLL1 and TTLL7, which have been indicated to be important for neuronal polarity. In this study, we constructed pure lines of Ttll1 and Ttll7 knockout mice. Ttll knockout mice showed several abnormal behaviors. Matrix-assisted laser desorption/ionization (MALDI) Imaging mass spectrometry (IMS) analyses of these brains showed increases in glutamate, suggesting that tubulin polyglutamylation by these TTLLs acts as a pool of glutamate in neurons and modulates some other amino acids related to glutamate. Full article
(This article belongs to the Special Issue Glutamate and Glutamate Receptors in Health and Diseases)
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Review

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26 pages, 2632 KiB  
Review
Glutamate Receptor Dysregulation and Platelet Glutamate Dynamics in Alzheimer’s and Parkinson’s Diseases: Insights into Current Medications
by Deepa Gautam, Ulhas P. Naik, Meghna U. Naik, Santosh K. Yadav, Rameshwar Nath Chaurasia and Debabrata Dash
Biomolecules 2023, 13(11), 1609; https://doi.org/10.3390/biom13111609 - 3 Nov 2023
Cited by 2 | Viewed by 1755
Abstract
Two of the most prevalent neurodegenerative disorders (NDDs), Alzheimer’s disease (AD) and Parkinson’s disease (PD), present significant challenges to healthcare systems worldwide. While the etiologies of AD and PD differ, both diseases share commonalities in synaptic dysfunction, thereby focusing attention on the role [...] Read more.
Two of the most prevalent neurodegenerative disorders (NDDs), Alzheimer’s disease (AD) and Parkinson’s disease (PD), present significant challenges to healthcare systems worldwide. While the etiologies of AD and PD differ, both diseases share commonalities in synaptic dysfunction, thereby focusing attention on the role of neurotransmitters. The possible functions that platelets may play in neurodegenerative illnesses including PD and AD are becoming more acknowledged. In AD, platelets have been investigated for their ability to generate amyloid-ß (Aß) peptides, contributing to the formation of neurotoxic plaques. Moreover, platelets are considered biomarkers for early AD diagnosis. In PD, platelets have been studied for their involvement in oxidative stress and mitochondrial dysfunction, which are key factors in the disease’s pathogenesis. Emerging research shows that platelets, which release glutamate upon activation, also play a role in these disorders. Decreased glutamate uptake in platelets has been observed in Alzheimer’s and Parkinson’s patients, pointing to a systemic dysfunction in glutamate handling. This paper aims to elucidate the critical role that glutamate receptors play in the pathophysiology of both AD and PD. Utilizing data from clinical trials, animal models, and cellular studies, we reviewed how glutamate receptors dysfunction contributes to neurodegenerative (ND) processes such as excitotoxicity, synaptic loss, and cognitive impairment. The paper also reviews all current medications including glutamate receptor antagonists for AD and PD, highlighting their mode of action and limitations. A deeper understanding of glutamate receptor involvement including its systemic regulation by platelets could open new avenues for more effective treatments, potentially slowing disease progression and improving patient outcomes. Full article
(This article belongs to the Special Issue Glutamate and Glutamate Receptors in Health and Diseases)
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