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Keywords = glutamatergic synaptic transmission

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12 pages, 2075 KiB  
Communication
Pharmacological Interaction of Botulinum Neurotoxins with Excitatory and Inhibitory Neurotransmitter Systems Involved in the Modulation of Inflammatory Pain
by Sara Marinelli, Flaminia Pavone and Siro Luvisetto
Toxins 2025, 17(8), 374; https://doi.org/10.3390/toxins17080374 - 28 Jul 2025
Viewed by 265
Abstract
Botulinum neurotoxins (BoNTs) are known to inhibit synaptic transmission by targeting SNARE proteins, but their selectivity toward central excitatory and inhibitory pathways is not yet fully understood. In this study, the interaction of serotypes A (BoNT/A) and B (BoNT/B) with the glutamatergic and [...] Read more.
Botulinum neurotoxins (BoNTs) are known to inhibit synaptic transmission by targeting SNARE proteins, but their selectivity toward central excitatory and inhibitory pathways is not yet fully understood. In this study, the interaction of serotypes A (BoNT/A) and B (BoNT/B) with the glutamatergic and GABAergic systems has been investigated using a pharmacological approach in an animal model of inflammatory pain, i.e., the formalin test in mice. BoNTs were administered intracerebroventricularly, three days before testing, followed 15 min before testing by systemic administration of sub-analgesic doses of MK801, an NMDA receptor antagonist, or muscimol, a GABA_A receptor agonist. BoNT/A reduced the second phase of the formalin test without affecting both the first phase and the interphase, suggesting a selective action on excitatory glutamatergic circuits while sparing GABAergic inhibition. Co-administration of MK801 with BoNT/A did not enhance analgesia, and muscimol did not further reduce interphase, confirming preserved GABAergic transmission. In contrast, BoNT/B abolished the interphase, consistent with impaired GABA release. Co-administration of MK801 or muscimol with BoNT/B restored the interphase, indicating compensatory rebalancing of excitatory-inhibitory networks. These results demonstrate that BoNT/A and BoNT/B exert distinct effects on central neurotransmission and support the hypothesis that BoNT/A preferentially targets excitatory synapses, while BoNT/B targets inhibitory synapses. This work contributes to a deeper understanding of anti-inflammatory mechanisms of BoNTs and their selective interaction with central pain pathways. Full article
(This article belongs to the Special Issue Botulinum Toxins: New Uses in the Treatment of Diseases (2nd Edition))
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20 pages, 1301 KiB  
Review
The Involvement of the Endocannabinoid, Glutamatergic, and GABAergic Systems in PTSD
by Anna Dorota Grzesińska
Int. J. Mol. Sci. 2025, 26(13), 5929; https://doi.org/10.3390/ijms26135929 - 20 Jun 2025
Viewed by 737
Abstract
Post-traumatic stress disorder (PTSD) is a debilitating mental health condition that develops in response to traumatic events. The endocannabinoid, glutamatergic, and GABAergic systems play crucial roles in the neurobiological mechanisms of PTSD. Both the endocannabinoid, glutamatergic, and GABAergic systems are involved in synaptic [...] Read more.
Post-traumatic stress disorder (PTSD) is a debilitating mental health condition that develops in response to traumatic events. The endocannabinoid, glutamatergic, and GABAergic systems play crucial roles in the neurobiological mechanisms of PTSD. Both the endocannabinoid, glutamatergic, and GABAergic systems are involved in synaptic remodeling and neuronal differentiation, ensuring efficient information transmission in the brain. Their interplay influences motivation, behavior, sensory perception, pain regulation, and visual processing. Additionally, these systems regulate processes such as cellular proliferation, adhesion, apoptosis, and immune responses. This article explores the involvement of the endocannabinoid, glutamatergic, and GABAergic systems in PTSD pathogenesis. A literature review was conducted on studies examining the relationship between the endocannabinoid, glutamatergic, and GABAergic systems in PTSD. Relevant publications were sourced from the Web of Science and Scopus databases, covering research up to 29 February 2025. Neurobiological mechanisms underlying PTSD may share common pathways with other mental and somatic disorders, particularly those involving inflammatory processes. The identification of biomarkers is crucial for assessing PTSD risk and implementing targeted interventions to improve patient outcomes. A deeper understanding of these mechanisms could enhance therapeutic strategies, ultimately improving the quality of life for individuals affected by PTSD. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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21 pages, 3323 KiB  
Article
Subcortical Circuits Among Pedunculopontine Nucleus, Thalamus and Basal Ganglia Play Important Roles in Paroxysmal Arousal in Genetic Rat Models of Autosomal Dominant Sleep-Related Hypermotor Epilepsy
by Ruri Okubo, Eishi Motomura and Motohiro Okada
Int. J. Mol. Sci. 2025, 26(12), 5522; https://doi.org/10.3390/ijms26125522 - 9 Jun 2025
Viewed by 330
Abstract
A part of autosomal dominant sleep-related hypermotor epilepsy (ADSHE) is caused by mutant CHRNA4. The pathomechanisms underlying motor seizures followingly brief/sudden awakening (paroxysmal arousal) in ADSHE seizures remain to be clarified. This study determined extracellular levels of ACh and L-glutamate in the pedunculopontine [...] Read more.
A part of autosomal dominant sleep-related hypermotor epilepsy (ADSHE) is caused by mutant CHRNA4. The pathomechanisms underlying motor seizures followingly brief/sudden awakening (paroxysmal arousal) in ADSHE seizures remain to be clarified. This study determined extracellular levels of ACh and L-glutamate in the pedunculopontine nucleus (PPN) and its projection regions, including the thalamus and basal ganglia, during wakefulness, slow-wave sleep (SWS) and paroxysmal arousal of transgenic rats bearing rat S286L-mutant Chrna4 (S286L-TG), corresponding to human S284L-mutant CHRNA4, using microdialysis. The expression of connexin43 and pannexin1 in the plasma membrane of the PPN was determined using capillary immunoblotting. The expressions of connexin43 and pannexin1 in the PPN plasma membrane of S286L-TG were larger than the wild type. The extracellular L-glutamate levels in the PPN and projection regions of S286L-TG consistently increased during both wakefulness and SWS compared to the wild type. The extracellular levels of ACh and L-glutamate in the PPN and projection regions decreased accompaning SWS in the wild type. In S286L-TG, this decreasing extracellular ACh level was observed, whereas decreasing L-glutamate level was impaired. Both extracellular levels of ACh and L-glutamate in the PPN and projection regions drastically increased during paroxysmal arousal. Hemichannel inhibitors suppressed the increasing releases of ACh and L-glutamate induced by paroxysmal arousal but decreased and did not affect extracellular levels of L-glutamate and ACh during wakefulness and SWS, respectively. In particular, under hemichannels inhibition, decreasing L-glutamate release accompanying SWS was observed in S286L-TG. This study elucidated that enhanced hemichannels are predominantly involved in the dysfunction of glutamatergic transmission compared to AChergic transmission during the interictal stage in S286L-TG, whereas the hyperactivation of hemichannels contributes to the generation of paroxysmal arousal. Therefore, the hyperactivated excitatory tripartite synaptic transmission associated with hemichannels in the PPN and projection regions plays important roles in epileptogenesis/ictogenesis in S286L-TG. Full article
(This article belongs to the Special Issue Molecular Research in Epilepsy and Epileptogenesis—2nd Edition)
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19 pages, 1302 KiB  
Article
Exo70 Protects Against Memory and Synaptic Impairments Following Mild Traumatic Brain Injury
by Matías Lira, Jorge Abarca, Rodrigo G. Mira, Pedro Zamorano and Waldo Cerpa
Antioxidants 2025, 14(6), 640; https://doi.org/10.3390/antiox14060640 - 26 May 2025
Viewed by 531
Abstract
Mild traumatic brain injury (mTBI), a leading cause of disability in young adults, often results from external forces that damage the brain. Cellularly, mTBI induces oxidative stress, characterized by excessive reactive oxygen species (ROS) and diminished antioxidant capacity. This redox imbalance disrupts hippocampal [...] Read more.
Mild traumatic brain injury (mTBI), a leading cause of disability in young adults, often results from external forces that damage the brain. Cellularly, mTBI induces oxidative stress, characterized by excessive reactive oxygen species (ROS) and diminished antioxidant capacity. This redox imbalance disrupts hippocampal glutamatergic transmission and synaptic plasticity, where NMDA receptors (NMDARs) are crucial. The exocyst, a vesicle tethering complex, is implicated in glutamate receptor trafficking. We previously showed that Exo70, a key exocyst subunit, redistributes within synapses and increases its interaction with the NMDAR subunit GluN2B following mTBI, suggesting a role in GluN2B distribution from synaptic to extrasynaptic sites. This study investigated whether Exo70 could mitigate mTBI pathology by modulating NMDAR trafficking under elevated oxidative stress. Using a modified Maryland mTBI mouse model, we overexpressed Exo70 in CA1 pyramidal neurons via lentiviral transduction. Exo70 overexpression prevented mTBI-induced cognitive impairment, assessed by the Morris water maze. Moreover, these mice exhibited basal and NMDAR-dependent hippocampal synaptic transmission comparable to sham animals, preventing mTBI-induced deterioration. Preserved long-term potentiation, abundant synaptic GluN2B-containing NMDARs, and downstream signaling indicated that Exo70 overexpression prevented mTBI-related alterations. Our findings highlight Exo70’s crucial role in NMDAR trafficking, potentially counteracting oxidative stress effects. The exocyst complex may be a critical component of the machinery regulating NMDAR distribution in health and disease, particularly in pathologies featuring oxidative stress and NMDAR dysfunction, like mTBI. Full article
(This article belongs to the Special Issue Oxidative Stress in Brain Function—2nd Edition)
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17 pages, 6118 KiB  
Article
Birch Sap Preserves Memory Function in Rats by Enhancing Cerebral Blood Flow and Modulating the Presynaptic Glutamatergic System in the Hippocampus
by Chien-Fen Huang, Tzu-Kang Lin, Chia-Chuan Chang, Ming-Yi Lee, Ching-Yi Lu, Chi-Feng Hung and Su-Jane Wang
Int. J. Mol. Sci. 2025, 26(11), 5009; https://doi.org/10.3390/ijms26115009 - 22 May 2025
Viewed by 657
Abstract
As the average age of the population increases, memory impairment has become an increasingly prevalent issue. This study investigates the effects of 14 days of oral birch sap administration on memory functions in healthy rats using the Morris water maze (MWM) test and [...] Read more.
As the average age of the population increases, memory impairment has become an increasingly prevalent issue. This study investigates the effects of 14 days of oral birch sap administration on memory functions in healthy rats using the Morris water maze (MWM) test and explores the underlying mechanisms. A compositional analysis revealed that birch soap is rich in polysaccharides, specifically a low-molecular weight polysaccharide (MW 1.29 kDa), and exhibits no hepatotoxicity or renal toxicity at the tested dose. The results from the MWM test demonstrated that the time and distance required to reach the platform were significantly shorter in the birch sap-treated group compared to the control group, suggesting that birch sap supports memory preservation. Moreover, rats treated with birch sap showed improved cerebral blood flow compared to the control rats. Additionally, in hippocampal nerve terminals (synaptosomes), rats treated with birch sap exhibited a significant increase in evoked glutamate release, as well as elevated levels of presynaptic proteins, including vesicular glutamate transporter 1 (VGluT1), synaptophysin, synaptobrevin, synaptotagmin, syntaxin, synapsin I, and the 25 kDa synaptosome-associated protein (SNAP-25). Transmission electron microscopy also revealed a notable increase in the number of synaptic vesicles in hippocampal synaptosomes of the birch-sap-treated rats. These findings suggest that birch sap enhances hippocampal presynaptic glutamatergic functions and cerebral blood flow, contributing to its memory-preserving effects in rats. Full article
(This article belongs to the Special Issue Nutraceuticals for the Maintenance of Brain Health)
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22 pages, 4224 KiB  
Article
The Role of Glutamatergic Neurons in Changes of Synaptic Plasticity Induced by THz Waves
by Lequan Song, Ji Dong, Wenjing Cheng, Zhengjie Fei, Rui Wang, Zhiwei He, Junmiao Pan, Li Zhao, Hui Wang and Ruiyun Peng
Biomolecules 2025, 15(4), 532; https://doi.org/10.3390/biom15040532 - 4 Apr 2025
Viewed by 560
Abstract
Background: Terahertz (THz) waves, lying between millimeter waves and infrared light, may interact with biomolecules due to their unique energy characteristics. However, whether THz waves are neurally regulated remains controversial, and the underlying mechanism is elusive. Methods: Mouse brain slices were [...] Read more.
Background: Terahertz (THz) waves, lying between millimeter waves and infrared light, may interact with biomolecules due to their unique energy characteristics. However, whether THz waves are neurally regulated remains controversial, and the underlying mechanism is elusive. Methods: Mouse brain slices were exposed to 1.94 THz waves for 1 h. Synaptic plasticity was evaluated via transmission electron microscopy (TEM), long-term potentiation (LTP), and neuronal class III β-tubulin (Tuj1) and synaptophysin (SYN) expression. Immunofluorescence (IF) and electrophysiology were used to identify neurons sensitive to THz waves. The calcium activity of excitatory neurons, glutamate receptor currents, and glutamate neuron marker expression was also assessed using calcium imaging, a patch clamp, and Western blotting (WB). Optogenetics and chemogenetics were used to determine the role of excitatory neurons in synaptic plasticity impairment after THz wave exposure. NMDA receptor 2B (GluN2B) was overexpressed in the ventral hippocampal CA1 (vCA1) by a lentivirus to clarify the role of GluN2B in THz wave-induced synaptic plasticity impairment. Results: Exposure to 1.94 THz waves increased postsynaptic density (PSD) thickness and reduced the field excitatory postsynaptic potential (fEPSP) slope and Tuj1 and SYN expression. THz waves diminished vCA1 glutamatergic neuron activity and excitability, neural electrical activity, and glutamate transporter function. THz waves reduced N-methyl-D-aspartate receptor (NMDAR) current amplitudes and NMDAR subunit expression. Activating vCA1 glutamatergic neurons through optogenetics and chemogenetics mitigated THz wave-induced synaptic plasticity impairment. GluN2B subunit overexpression improved synaptic plasticity marker expression, synaptic ultrastructure, and the fEPSP slope. Conclusions: Exposure to 1.94 THz waves decreased synaptic plasticity, glutamatergic neuron excitability, and glutamatergic synaptic transmission in the vCA1. Glutamatergic neuron activation and GluN2B overexpression alleviated THz wave-induced synaptic plasticity impairment; thus, neuromodulation could be a promising therapeutic strategy to mitigate the adverse effects of THz radiation. Full article
(This article belongs to the Section Molecular Medicine)
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16 pages, 847 KiB  
Review
Therapeutic Effects of Pharmacological Modulation of Serotonin Brain System in Human Patients and Animal Models of Fragile X Syndrome
by Lucia Ciranna and Lara Costa
Int. J. Mol. Sci. 2025, 26(6), 2495; https://doi.org/10.3390/ijms26062495 - 11 Mar 2025
Viewed by 836
Abstract
The brain serotonin (5-HT) system modulates glutamatergic and GABAergic transmission in almost every brain area, crucially regulating mood, food intake, body temperature, pain, hormone secretion, learning and memory. Previous studies suggest a disruption of the brain 5-HT system in Fragile X Syndrome, with [...] Read more.
The brain serotonin (5-HT) system modulates glutamatergic and GABAergic transmission in almost every brain area, crucially regulating mood, food intake, body temperature, pain, hormone secretion, learning and memory. Previous studies suggest a disruption of the brain 5-HT system in Fragile X Syndrome, with abnormal activity of the 5-HT transporter leading to altered 5-HT brain levels. We provide an update on therapeutic effects exerted by drugs modulating serotonergic transmission on Fragile X patients and animal models. The enhancement of serotonergic transmission using Selective Serotonin Reuptake Inhibitors (SSRIs) corrected mood disorders and language deficits in Fragile X patients. In Fmr1 KO mice, a model of Fragile X Syndrome, selective 5-HT7 receptor agonists rescued synaptic plasticity, memory and stereotyped behavior. In addition, drugs specifically acting on 5-HT1A, 5-HT2 and 5-HT5 receptor subtypes were able to correct, respectively, epilepsy, learning deficits and hyperactivity in different Fragile X animal models. In conclusion, the SSRI treatment of Fragile X patients improves mood and language; in parallel, studies on animal models suggest that compounds selectively acting on distinct 5-HT receptor subtypes might provide a targeted correction of other Fragile X phenotypes, and thus should be further tested in clinical trials for future therapy. Full article
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24 pages, 2536 KiB  
Article
THz Waves Improve Spatial Working Memory by Increasing the Activity of Glutamatergic Neurons in Mice
by Lequan Song, Zhiwei He, Ji Dong, Haoyu Wang, Jing Zhang, Binwei Yao, Xinping Xu, Hui Wang, Li Zhao and Ruiyun Peng
Cells 2025, 14(5), 370; https://doi.org/10.3390/cells14050370 - 3 Mar 2025
Viewed by 964
Abstract
Terahertz (THz) waves, a novel type of radiation with quantum and electronic properties, have attracted increasing attention for their effects on the nervous system. Spatial working memory, a critical component of higher cognitive function, is coordinated by brain regions such as the infralimbic [...] Read more.
Terahertz (THz) waves, a novel type of radiation with quantum and electronic properties, have attracted increasing attention for their effects on the nervous system. Spatial working memory, a critical component of higher cognitive function, is coordinated by brain regions such as the infralimbic cortex (IL) region of the medial prefrontal cortex and the ventral cornu ammonis 1 (vCA1) of hippocampus. However, the regulatory effects of THz waves on spatial working memory and the underlying mechanisms remain unclear. In this study, the effects of 0.152 THz waves on glutamatergic neuronal activity and spatial working memory and the related mechanisms were investigated in cell, brain slice, and mouse models. Cellular experiments revealed that THz waves exposure for 60 min significantly increased the intrinsic excitability of primary hippocampal neurons, enhanced glutamatergic neuron activity, and upregulated the expression of molecules involved in glutamate metabolism. In brain slice experiments, THz waves markedly elevated neuronal activity, promoted synaptic plasticity, and increased glutamatergic synaptic transmission within the IL and vCA1 regions. Molecular dynamics simulations found that THz waves could inhibit the ion transport function of glutamate receptors. Moreover, Y-maze tests demonstrated that mice exposed to THz waves exhibited significantly improved spatial working memory. Multiomics analyses indicated that THz waves could induce changes in chromatin accessibility and increase the proportion of excitatory neurons. These findings suggested that exposure to 0.152 THz waves increased glutamatergic neuronal activity, promoted synaptic plasticity, and improved spatial working memory, potentially through modifications in chromatin accessibility and excitatory neuron proportions. Full article
(This article belongs to the Section Cells of the Nervous System)
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19 pages, 8543 KiB  
Article
ATAD1 Regulates Neuronal Development and Synapse Formation Through Tuning Mitochondrial Function
by Hao-Hao Yan, Jia-Jia He, Chuanhai Fu, Jia-Hui Chen and Ai-Hui Tang
Int. J. Mol. Sci. 2025, 26(1), 44; https://doi.org/10.3390/ijms26010044 - 24 Dec 2024
Cited by 1 | Viewed by 1282
Abstract
Mitochondrial function is essential for synaptic function. ATAD1, an AAA+ protease involved in mitochondrial quality control, governs fission–fusion dynamics within the organelle. However, the distribution and functional role of ATAD1 in neurons remain poorly understood. In this study, we demonstrate that ATAD1 is [...] Read more.
Mitochondrial function is essential for synaptic function. ATAD1, an AAA+ protease involved in mitochondrial quality control, governs fission–fusion dynamics within the organelle. However, the distribution and functional role of ATAD1 in neurons remain poorly understood. In this study, we demonstrate that ATAD1 is primarily localized to mitochondria in dendrites and, to a lesser extent, in spines in cultured hippocampal neurons. We found that ATAD1 deficiency disrupts the mitochondrial fission–fusion balance, resulting in mitochondrial fragmentation. This deficiency also impairs dendritic branching, hinders dendritic spine maturation, and reduces glutamatergic synaptic transmission in hippocampal neuron. To further investigate the underlying mechanism, we employed an ATP hydrolysis-deficient mutant of ATAD1 to rescue the neuronal deficits associated with ATAD1 loss. We discovered that the synaptic deficits are independent of the mitochondrial morphology changes but rely on its ATP hydrolysis. Furthermore, we show that ATAD1 loss leads to impaired mitochondrial function, including decreased ATP production, impaired membrane potential, and elevated oxidative stress. In conclusion, our results provide evidence that ATAD1 is crucial for maintaining mitochondrial function and regulating neurodevelopment and synaptic function. Full article
(This article belongs to the Special Issue New Insights into Mitochondria in Health and Diseases)
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15 pages, 3634 KiB  
Article
Chemogenetic Inhibition of Prefrontal Cortex Ameliorates Autism-Like Social Deficits and Absence-Like Seizures in a Gene-Trap Ash1l Haploinsufficiency Mouse Model
by Kaijie Ma, Kylee McDaniel, Daoqi Zhang, Maria Webb and Luye Qin
Genes 2024, 15(12), 1619; https://doi.org/10.3390/genes15121619 - 18 Dec 2024
Viewed by 1110
Abstract
Background: ASH1L (absent, small, or homeotic-like 1), a histone methyltransferase, has been identified as a high-risk gene for autism spectrum disorder (ASD). We previously showed that postnatal Ash1l severe deficiency in the prefrontal cortex (PFC) of male and female mice caused seizures. However, [...] Read more.
Background: ASH1L (absent, small, or homeotic-like 1), a histone methyltransferase, has been identified as a high-risk gene for autism spectrum disorder (ASD). We previously showed that postnatal Ash1l severe deficiency in the prefrontal cortex (PFC) of male and female mice caused seizures. However, the synaptic mechanisms underlying autism-like social deficits and seizures need to be elucidated. Objective: The goal of this study is to characterize the behavioral deficits and reveal the synaptic mechanisms in an Ash1l haploinsufficiency mouse model using a targeted gene-trap knockout (gtKO) strategy. Method: A series of behavioral tests were used to examine behavioral deficits. Electrophysiological and chemogenetic approaches were used to examine and manipulate the excitability of pyramidal neurons in the PFC of Ash1l+/GT mice. Results: Ash1l+/GT mice displayed social deficits, increased self-grooming, and cognitive impairments. Epileptiform discharges were found on electroencephalograms (EEGs) of Ash1l+/GT mice, indicating absence-like seizures. Ash1l haploinsufficiency increased the susceptibility for convulsive seizures when Ash1l+/GT mice were challenged by pentylenetetrazole (PTZ, a competitive GABAA receptor antagonist). Whole-cell patch-clamp recordings showed that Ash1l haploinsufficiency increased the excitability of pyramidal neurons in the PFC by altering intrinsic neuronal properties, enhancing glutamatergic synaptic transmission, and diminishing GABAergic synaptic inhibition. Chemogenetic inhibition of pyramidal neurons in the PFC of Ash1l+/GT mice ameliorated autism-like social deficits and abolished absence-like seizures. Conclusions: We demonstrated that increased neural activity in the PFC contributed to the autism-like social deficits and absence-like seizures in Ash1l+/GT mice, which provides novel insights into the therapeutic strategies for patients with ASH1L-associated ASD and epilepsy. Full article
(This article belongs to the Special Issue The Genetic and Epigenetic Basis of Neurodevelopmental Disorders)
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21 pages, 296 KiB  
Review
The Role of Brain Plasticity in Neuromuscular Disorders: Current Knowledge and Future Prospects
by Paolo Alonge, Giulio Gadaleta, Guido Urbano, Antonino Lupica, Vincenzo Di Stefano, Filippo Brighina and Angelo Torrente
Brain Sci. 2024, 14(10), 971; https://doi.org/10.3390/brainsci14100971 - 26 Sep 2024
Viewed by 1598
Abstract
Background/Objectives: Increasing evidence shows an involvement of brain plasticity mechanisms in both motor and central manifestations of neuromuscular disorders (NMDs). These mechanisms could be specifically addressed with neuromodulation or rehabilitation protocols. The aim of this scoping review is to summarise the evidence [...] Read more.
Background/Objectives: Increasing evidence shows an involvement of brain plasticity mechanisms in both motor and central manifestations of neuromuscular disorders (NMDs). These mechanisms could be specifically addressed with neuromodulation or rehabilitation protocols. The aim of this scoping review is to summarise the evidence on plasticity mechanisms’ involvement in NMDs to encourage future research. Methods: A scoping review was conducted searching the PubMed and Scopus electronic databases. We selected papers addressing brain plasticity and central nervous system (CNS) studies through non-invasive brain stimulation techniques in myopathies, muscular dystrophies, myositis and spinal muscular atrophy. Results: A total of 49 papers were selected for full-text examination. Regardless of the variety of pathogenetic and clinical characteristics of NMDs, studies show widespread changes in intracortical inhibition mechanisms, as well as disruptions in glutamatergic and GABAergic transmission, resulting in altered brain plasticity. Therapeutic interventions with neurostimulation techniques, despite being conducted only anecdotally or on small samples, show promising results; Conclusions: despite challenges posed by the rarity and heterogeneity of NMDs, recent evidence suggests that synaptic plasticity may play a role in the pathogenesis of various muscular diseases, affecting not only central symptoms but also strength and fatigue. Key questions remain unanswered about the role of plasticity and its potential as a therapeutic target. As disease-modifying therapies advance, understanding CNS involvement in NMDs could lead to more tailored treatments. Full article
(This article belongs to the Special Issue Computational Intelligence and Brain Plasticity)
20 pages, 1993 KiB  
Article
Cannabinol (CBN) Influences the Ion Channels and Synaptic-Related Genes in NSC-34 Cell Line: A Transcriptomic Study
by Alessandra Trainito, Claudia Muscarà, Agnese Gugliandolo, Luigi Chiricosta, Stefano Salamone, Federica Pollastro, Emanuela Mazzon and Simone D’Angiolini
Cells 2024, 13(18), 1573; https://doi.org/10.3390/cells13181573 - 19 Sep 2024
Cited by 3 | Viewed by 1746
Abstract
Neurological disorders such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis, and schizophrenia are associated with altered neuronal excitability, resulting from dysfunctions in the molecular architecture and physiological regulation of ion channels and synaptic transmission. Ion channels and synapses are regarded as suitable therapeutic targets [...] Read more.
Neurological disorders such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis, and schizophrenia are associated with altered neuronal excitability, resulting from dysfunctions in the molecular architecture and physiological regulation of ion channels and synaptic transmission. Ion channels and synapses are regarded as suitable therapeutic targets in modern pharmacology. Cannabinoids have received great attention as an original therapeutic approach for their effects on human health due to their ability to modulate the neurotransmitter release through interaction with the endocannabinoid system. In our study, we explored the effect of cannabinol (CBN) through next-generation sequencing analysis of NSC-34 cell physiology. Our findings revealed that CBN strongly influences the ontologies related to ion channels and synapse activity at all doses tested. Specifically, the genes coding for calcium and potassium voltage-gated channel subunits, and the glutamatergic and GABAergic receptors (Cacna1b, Cacna1h, Cacng8, Kcnc3, Kcnd1, Kcnd2, Kcnj4, Grik5, Grik1, Slc17a7, Gabra5), were up-regulated. Conversely, the genes involved into serotoninergic and cholinergic pathways (Htr3a, Htr3b, Htr1b, Chrna3, Chrnb2, Chrnb4), were down-regulated. These findings highlight the influence of CBN in the expression of genes involved into ion influx and synaptic transmission. Full article
(This article belongs to the Special Issue Ion Channel Involvement in Neurological and Neuromuscular Disorders)
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20 pages, 7429 KiB  
Article
MC4R Localizes at Excitatory Postsynaptic and Peri-Postsynaptic Sites of Hypothalamic Neurons in Primary Culture
by Haven Griffin, Jude Hanson, Kevin D. Phelan and Giulia Baldini
Cells 2024, 13(15), 1235; https://doi.org/10.3390/cells13151235 - 23 Jul 2024
Cited by 2 | Viewed by 2118
Abstract
The melanocortin-4 receptor (MC4R) is a G protein-coupled receptor (GPCR) that is expressed in several brain locations encompassing the hypothalamus and the brainstem, where the receptor controls several body functions, including metabolism. In a well-defined pathway to decrease appetite, hypothalamic proopiomelanocortin (POMC) neurons [...] Read more.
The melanocortin-4 receptor (MC4R) is a G protein-coupled receptor (GPCR) that is expressed in several brain locations encompassing the hypothalamus and the brainstem, where the receptor controls several body functions, including metabolism. In a well-defined pathway to decrease appetite, hypothalamic proopiomelanocortin (POMC) neurons localized in the arcuate nucleus (Arc) project to MC4R neurons in the paraventricular nuclei (PVN) to release the natural MC4R agonist α-melanocyte-stimulating hormone (α-MSH). Arc neurons also project excitatory glutamatergic fibers to the MC4R neurons in the PVN for a fast synaptic transmission to regulate a satiety pathway potentiated by α-MSH. By using super-resolution microscopy, we found that in hypothalamic neurons in a primary culture, postsynaptic density protein 95 (PSD95) colocalizes with GluN1, a subunit of the ionotropic N-methyl-D-aspartate receptor (NMDAR). Thus, hypothalamic neurons form excitatory postsynaptic specializations. To study the MC4R distribution at these sites, tagged HA-MC4R under the synapsin promoter was expressed in neurons by adeno-associated virus (AAV) gene transduction. HA-MC4R immunofluorescence peaked at the center and in proximity to the PSD95- and NMDAR-expressing sites. These data provide morphological evidence that MC4R localizes together with glutamate receptors at postsynaptic and peri-postsynaptic sites. Full article
(This article belongs to the Special Issue Advances in Neurogenesis: 2nd Edition)
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20 pages, 3789 KiB  
Article
Firing Patterns of Mitral Cells and Their Transformation in the Main Olfactory Bulb
by Ze-Jun Wang, Liqin Sun and Thomas Heinbockel
Brain Sci. 2024, 14(7), 678; https://doi.org/10.3390/brainsci14070678 - 3 Jul 2024
Viewed by 1704
Abstract
Mitral cells (MCs) in the main olfactory bulb relay odor information to higher-order olfactory centers by encoding the information in the form of action potentials. The firing patterns of these cells are influenced by both their intrinsic properties and their synaptic connections within [...] Read more.
Mitral cells (MCs) in the main olfactory bulb relay odor information to higher-order olfactory centers by encoding the information in the form of action potentials. The firing patterns of these cells are influenced by both their intrinsic properties and their synaptic connections within the neural network. However, reports on MC firing patterns have been inconsistent, and the mechanisms underlying these patterns remain unclear. Using whole-cell patch-clamp recordings in mouse brain slices, we discovered that MCs exhibit two types of integrative behavior: regular/rhythmic firing and bursts of action potentials. These firing patterns could be transformed both spontaneously and chemically. MCs with regular firing maintained their pattern even in the presence of blockers of fast synaptic transmission, indicating this was an intrinsic property. However, regular firing could be transformed into bursting by applying GABAA receptor antagonists to block inhibitory synaptic transmission. Burst firing could be reverted to regular firing by blocking ionotropic glutamate receptors, rather than applying a GABAA receptor agonist, indicating that ionotropic glutamatergic transmission mediated this transformation. Further experiments on long-lasting currents (LLCs), which generated burst firing, also supported this mechanism. In addition, cytoplasmic Ca2+ in MCs was involved in the transformation of firing patterns mediated by glutamatergic transmission. Metabotropic glutamate receptors also played a role in LLCs in MCs. These pieces of evidence indicate that odor information can be encoded on a mitral cell (MC) platform, where it can be relayed to higher-order olfactory centers through intrinsic and dendrodendritic mechanisms in MCs. Full article
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22 pages, 1209 KiB  
Review
Glutamate-Mediated Excitotoxicity in the Pathogenesis and Treatment of Neurodevelopmental and Adult Mental Disorders
by Noemi Nicosia, Mattia Giovenzana, Paulina Misztak, Jessica Mingardi and Laura Musazzi
Int. J. Mol. Sci. 2024, 25(12), 6521; https://doi.org/10.3390/ijms25126521 - 13 Jun 2024
Cited by 31 | Viewed by 9227
Abstract
Glutamate is the main excitatory neurotransmitter in the brain wherein it controls cognitive functional domains and mood. Indeed, brain areas involved in memory formation and consolidation as well as in fear and emotional processing, such as the hippocampus, prefrontal cortex, and amygdala, are [...] Read more.
Glutamate is the main excitatory neurotransmitter in the brain wherein it controls cognitive functional domains and mood. Indeed, brain areas involved in memory formation and consolidation as well as in fear and emotional processing, such as the hippocampus, prefrontal cortex, and amygdala, are predominantly glutamatergic. To ensure the physiological activity of the brain, glutamatergic transmission is finely tuned at synaptic sites. Disruption of the mechanisms responsible for glutamate homeostasis may result in the accumulation of excessive glutamate levels, which in turn leads to increased calcium levels, mitochondrial abnormalities, oxidative stress, and eventually cell atrophy and death. This condition is known as glutamate-induced excitotoxicity and is considered as a pathogenic mechanism in several diseases of the central nervous system, including neurodevelopmental, substance abuse, and psychiatric disorders. On the other hand, these disorders share neuroplasticity impairments in glutamatergic brain areas, which are accompanied by structural remodeling of glutamatergic neurons. In the current narrative review, we will summarize the role of glutamate-induced excitotoxicity in both the pathophysiology and therapeutic interventions of neurodevelopmental and adult mental diseases with a focus on autism spectrum disorders, substance abuse, and psychiatric disorders. Indeed, glutamatergic drugs are under preclinical and clinical development for the treatment of different mental diseases that share glutamatergic neuroplasticity dysfunctions. Although clinical evidence is still limited and more studies are required, the regulation of glutamate homeostasis is attracting attention as a potential crucial target for the control of brain diseases. Full article
(This article belongs to the Special Issue Mechanisms of Neurotoxicity)
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