AIP Advances
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2024
·Vol. 14
·期 8
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IF 1.4
Zheng Yu,Song Rujuan,Wei Shengjie,Dong Lei,Chen Yazhou
Long-term potentiation (LTP) in the Schaffer-CA1 region of the hippocampus is closely related to learning and memory. Magnetic stimulation, as an effective physical means of regulating synaptic plasticity, has received widespread attention. However, research on the mechanism of the effect of different frequencies of magnetic fields (MFs) on LTP is relatively scarce. This article focuses on Ca 2+ , Na + , K + , NMDA receptors, and AMPA receptors that play important roles in the process of MF regulation of LTP. A combined electrophysiological and pharmacological approach was used to identify Ca 2+ as a key factor in the modulation of LTP by MFs of different frequencies. Subsequently, further experiments revealed that low levels of intracellular Ca 2+ concentration ([Ca 2+ ] i ) intensified the inhibition of low-frequency MFs on LTP, while high levels of [Ca 2+ ] i enhanced the promotion effect of high-frequency MFs on LTP, indicating a positive correlation between [Ca 2+ ] i levels and MF regulation of LTP levels. The research results of this article may help explore the deeper relationship between different frequencies of MFs and synaptic plasticity, and they also have a certain reference value for magnetic stimulation therapy in the treatment of neurological diseases related to LTP injury or learning and memory deficits.
研究领域:
神经科学
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医学
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产品关联
DOI
高影响因子
BEHAVIOURAL BRAIN RESEARCH
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2025
·
IF 2.3
Yue-Heng Yan,Hong-Kun Wang,Zi-Hao Wang,Rui-Ze Wang,Ruo-Xuan Li,Li-Li Huang,Yan-Yan Wang
NMDA receptors (NMDAR) are vital in CNS activities such as anxiety, memory, and cognition, and the neurobiological mechanisms behind anxiety disorders are exceedingly complicated. The "glutamic acid theory" posits that glutamate excitotoxicity is a key pathophysiological mechanism in anxiety disorders. However, the exact mechanism by which conditioned fear contributes to anxiety disorders remains unknown.Based on the conditioned fear-induced anxiety disorder model, this work aims to investigate changes in NMDAR and related proteins throughout the acquisition and expression of fear memory, as well as the impact on synaptic structural and functional plasticity. Injecting the NMDA receptor endogenous agonist D-Serine (50 μg/μL) and the noncompetitive antagonist MK-801 (1 μg/μL) into the lateral ventricle of the conditioned fear model rats, as well as conducting behavioral observations, show that NMDAR are closely involved in the development of conditioned fear-induced anxiety. Model rats showed significant changes in glutamate (Glu) and γ-aminobutyric acid (GABA) levels in the amygdala (BLA), as well as expression of NMDAR and downstream BDNF/TrkB signaling pathway components. At the same time, model rats exhibited synaptic and neuronal injury, aberrant long-term potentiation (LTP), and decreased expression of essential synaptic proteins SYP and PSD-95. In conclusion, our study demonstrates that NMDAR and synaptic plasticity play a critical role in the development of conditioned fear-induced anxiety, serving as an important reference for understanding the neurobiological underpinnings of anxiety disorders and providing insights into their treatment and new possible targets.
研究领域:
神经科学
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行为学
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分子生物学
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DOI
PubMed
高影响因子
MOLECULES
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2018
·Vol. 23
·期 5
·996
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IF 3.098
Wenchao Li,Jingjian Liu,Minghua Fan,Zhongtang Li,Yin Chen,Guisen Zhang,Zhuo Huang,Liangren Zhang
GLYX-13, a NMDAR glycine-site partial agonist, was discovered as a promising antidepressant with rapidly acting effects but no ketamine-like side effects. However, the reported synthetic process route had deficiencies of low yield and the use of unfriendly reagents. Here, we report a scaled-up synthesis of GLYX-13 with an overall yield of 30% on the hectogram scale with a column chromatography-free strategy, where the coupling and deprotection reaction conditions were systematically optimized. Meanwhile, the absolute configuration of precursor compound of GLYX-13 was identified by X-ray single crystal diffraction. Finally, the activity of GLYX-13 was verified in the cortical neurons of mice through whole-cell voltage-clamp technique.Keywords:GLYX-13;NMDA receptor;chromatography-free synthesis;crystal structure;whole-cell voltage-clamp
研究领域:
药理学
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合成化学
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神经科学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2024
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IF 7.7
Gong Chen,Panyang Gu,Wenfang Wu,Yuan Yin,Liangyu Pan,Shu Huang,Wei Lin,Meichun Deng
Histone methylations play a crucial role in the development of neuropathic pain, and SET domain containing 2 (SETD2), a histone methyltransferase, serves as the sole tri-methylase known to catalyze H3K36me3 at the gene body. The N -methyl- d -aspartate receptor (NMDAR) is activated and mediates excitatory synaptic transmission in neuropathic pain. Nevertheless, the involvement of SETD2 in neuropathic pain and the specific regulatory mechanisms affecting NMDARs remain poorly understood. The expression levels of SETD2 were significantly decreased in the spinal cord and dorsal root ganglion (DRG) of rodents undergoing neuropathic pain induced by sciatic nerve chronic constrictive injury. Lentiviral shRNA-mediated SETD2 knockdown and conditional knockout in sensory neurons caused sustained NMDAR upregulation in DRG and spinal cord, which resulted in heightened neuronal excitability and increased pain hypersensitivity. SETD2 deficiency also led to reduced H3K36me3 deposition within the Grin1 (glutamate ionotropic receptor NMDA type subunit 1) gene body, thereby promoting aberrant transcription of the NMDARs subunit GluN1. The absence of SETD2 in the DRG potentiated neuronal excitability and increased presynaptic NMDAR activity in the spinal dorsal horn. Chromatin immunoprecipitation sequencing targeting H3K36me3 identified NFAT5 as a co-transcription factor in the transcriptional regulation of Grin1 . These findings highlight SETD2 as a key regulator in pain signal transmission and offered new perspectives on the development of analgesics through the targeted modulation of epigenetic mechanisms.
研究领域:
神经科学
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表观遗传学
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疼痛研究
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产品关联
DOI
PubMed
高影响因子
NEUROCHEMICAL RESEARCH
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2025
·Vol. 50
·期 2
·1-13
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IF 3.8
Wang Jun,Zhang Nan,Liu Hong-Zheng,Wang Jin-Liang,Zhang Yong-Bo,Su Dong-Dong,Zhang Li-Min,Li Bao-Dong,Miao Hui-Tao,Miao Jun
Neuropathic pain (NP) imposes a significant burden on individuals, manifesting as nociceptive anaphylaxis, hypersensitivity, and spontaneous pain. Previous studies have shown that traumatic stress in the nervous system can lead to excessive production of hydrogen sulfide (H 2 S) in the gut. As a toxic gas, it can damage the nervous system through the gut-brain axis. However, whether traumatic stress in the nervous system leading to excessive production of H 2 S in the gut can ultimately cause neuropathic pain through the gut-brain axis remains to be investigated. This study established a model of chronic constriction injury (CCI) in mice to determine its effects on gut H 2 S production, the associated damage via the gut-brain axis, the potential neuropathic pain, as well as the probable mechanism. A CCI mouse model was developed using a spinal nerve ligation approach. Subsequently, the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were used to determine the mice’s pain thresholds. A variety of assays were performed, including immunofluorescence, western blotting, real-time quantitative Polymerase Chain Reaction (PCR), and membrane clamp whole-cell recordings. Mice subjected to CCI showed decreased MWT and TWL, decreased ZO-1 staining, decreased HuD staining, increased Glial fibrillary acidic protein (GFAP) staining, increased expression of tumor necrosis factor-alpha (TNF-α) protein and interleukin-6 (IL-6) protein, increased expression of NMDAR2B (NR2B) protein and NR2B mRNA, increased colocalization of vGlut2- and c-fos-positive cells, and a higher amplitude of evoked excitatory postsynaptic potential (EPSP) compared to Sham group. These changes were significantly reversed by H 2 S inhibitor treatment, and the specific NMDA receptor inhibitor MK-801 effectively restored the neurotoxicity of H 2 S. H 2 S is involved in CCI-induced neuropathic pain in mice, which might be mediated by the activation of the NMDA signaling pathway.
研究领域:
医学
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神经科学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
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2023
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IF 4.4
Meixi He,Yi Wang,Xiaozhe Zhang,Lihua Zhang
The N-methyl-d-aspartic acid (NMDA) receptors belongs to the family of ionotropic glutamate receptors, which could mediate most excitatory synaptic transmission in the brain. It is interesting to know if some available drugs have regulatory effects on the NMDARs. Herein, the present study reports the discovery of drugs targeting NMDAR using virtual screening. In this study, talniflumate with the EC50 value at 61.49 nM was successfully screened. The interaction analysis of this compound was further explored through molecular dynamics simulation. It is indicated that talniflumate could form stable interactions with GluN1-GluN2B NMDA receptors. In particular, H-bond interactions with high occupancies between GluN1-GluN2B NMDA receptors and talniflumate were observed. Compared to de novo drug discovery, this approach could be an alternative choice for development of safety and efficiency NMDAR inhibitors from available drugs.Communicated by Ramaswamy H. Sarma
研究领域:
神经科学
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药理学
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药物发现
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产品关联
DOI
PubMed
高影响因子
Molecular Medicine Reports
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2014
·Vol. 10
·期 1
·248-254
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IF 1.484
Xianwen Chen,Huang Li,Mingqing Huang,Mei Huang,Wei Xu,Kedan Chu,Lidian Chen,Yuqin Zhang
Gua Lou Gui Zhi decotion (GLGZD) has been reported to be an effective treatment for post‑apoplectic limb spasm in the clinic. The present study aimed to investigate whether GLGZD had an affect on cerebral injuries induced by middle cerebral artery occlusion (MCAO) in rats and its possible mechanism. High‑performance liquid chromatography was performed to analyze GLGZD. Furthermore, a model was established to assess the efficacy of GLGZD. Neurological defect scores and screen tests were analyzed. Brain ischemic infarct volume was measured using 2,3,5‑triphenyl tetrazolium chloride staining and glutamic acid (Glu), aspartic acid (Asp) and glycine (Gly) levels in the cerebrospinal fluid were measured using the Hitachi automatic amino acid analyzer. Immunohistochemistry was performed to determine the expression of the α‑amino‑3‑hydroxy‑5‑methyl‑4‑isoxazole‑propionic acid (AMPA) and N‑methyl‑D‑aspartic acid (NMDA) glutamate receptors, and to analyze histopathological change. GLGZD was found to improve neurological performance and reduce infarct volumes in MCAO rats. In addition, GLGZD was observed to enhance motor performance, which was assessed using the screen test. Furthermore, GLGZD was found to reduce Glu, Asp and Gly levels in the cerebrospinal fluid and downregulate the protein expression of the AMPA and NMDA glutamate receptors. Thus, it was demonstrated that GLGZD may exert neuroprotective effects through the modulation of excitatory amino acids, and AMPA and NMDA receptor expression.
研究领域:
神经科学
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中药学
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药理学
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DOI
PubMed
高影响因子
Science Bulletin
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2024
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IF 18.8
Xia Jie,Zhang Lixing,Zhu Wucheng,Tu Juchuanli,Peng Xilei,Deng Qiaodan,Li Siqin,He Xueyan,Dong Haonan,Liu Cuicui,Chen Xian,Xu Jiahui,Ma Wei,Xiao Yi,Liu Wen,Hu Guohong,Jiang Yi-Zhou,Chen Ceshi,Bian Xiu-Wu,Shao Zhi-Ming,Liu Suling
Neurotransmitters are increasingly recognized to play important roles in limiting anti-tumor immunity. N-acetyl-aspartyl-glutamate (NAAG) has been extensively studied in neurological disorders; however, its potential role in restricting anti-tumor immunity has not been investigated. Here, we demonstrated that NAAG or its synthetase RimK-like family member B (RIMKLB) significantly disrupted anti-tumor immunity by rewiring the myeloid progenitor differentiation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), which in turn promoted breast cancer growth and metastasis. Mechanistically, NAAG sustained the tumor immunosuppressive microenvironment by activating an NR2B-containing NMDA receptor (NR2B-NMDAR)-dependent p38-NOTCH1 axis, and subsequently stimulating tumor cell migration and invasion, as well as inducing PMN-MDSC differentiation and expansion. In mouse models, RIMKLB ablation or NMDAR inhibition enhanced the efficacy of anti-PD-1 therapy and suppressed tumor progression. An analysis of clinical samples revealed that high levels of NAAG and NR2B-NMDAR predicted a poor prognosis in TNBC patients. Collectively, our findings have uncovered a signaling role for tumor-derived NAAG beyond its classic function as a neurotransmitter that can be targeted pharmacologically to enhance immunotherapy against breast cancer.
研究领域:
肿瘤学
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免疫学
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生物化学
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分子生物学
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DOI
高影响因子
Neural Regeneration Research
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2020
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IF 3.171
Jian-Zhu Bo,Ling Xue,Shuang Li,Jing-Wen Yin,Zheng-Yao Li,Xi Wang,Jun-Feng Wang,Yan-Shu Zhang
Although exogenous D-serine has been applied as a neural regulatory intervention in many studies, the role played by D-serine in hippocampal injuries caused by lead exposure remains poorly understood. Rat models of chronic lead exposure were established through the administration of 0.05% lead acetate for 8 weeks. Simultaneously, rats were administered 30 or 60 mg/kg D-serine, intraperitoneally, twice a day. Our results showed that D-serine treatment shortened the escape latency from the Morris water maze, increased the number of times that mice crossed the original platform location, and alleviated the pathological damage experienced by hippocampal neurons in response to lead exposure. Although D-serine administration did not increase the expression levels of the N-methyl-D-aspartate receptor subtype 2B (NR2B) in the hippocampi of lead-exposed rats, 60 mg/kg D-serine treatment restored the expression levels of NR2A, which are reduced by lead exposure. These findings suggested that D-serine can alleviate learning and memory impairments induced by lead exposure and that the underlying mechanism is associated with the increased expression of NR2A in the hippocampus. This study was approved by the Animal Ethics Committee of North China University of Science and Technology, China (approval No. LX2018155) on December 21, 2018.
研究领域:
神经科学
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毒理学
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药理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2024
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IF 4.8
Jingbin Chen,Yali Liu,Yonggui Song,Huihui Liang,Genhua Zhu,Bike Zhang,Liangliang Liao,Jian Luo,Ming Yang,Dan Su
Ethnopharmacological relevance Citri Reticulata Pericarpium Viride (also known Qing-Pi or QP) is a plant in the Rutaceae family, QP is a traditional Qi-regulating medicine in Chinese medicine that is compatible with other Chinese medicine components and has extensive clinical practice in treating anxiety and depression. Reports on the pharmacological effects of QP have demonstrated its neuroprotective effects and antioxidant capacities. Numerous pharmacological benefits of QP are attributed to its antioxidant abilities. Anxiety disorders are a broadly defined category of mental illnesses. Oxidative stress and an imbalance in the antioxidant defense system are typical pathological features of these disorders. Aim of the study The aim of this study was to evaluate the effects of QP essential oil on anxiety using animal models and investigate the underlying neurobiological mechanisms. Materials and methods This study aimed to develop an animal model of anxiety using chronic restraint stress and investigate the effects of inhalation of Citri Reticulata Pericarpium Viride essential oil on anxiety-like behavior, olfactory function, and olfactory bulb neurogenesis in mice with anxiety. Results The results showed that long-term chronic restraint stimulation caused a decrease in olfactory function, significant anxiety-like behavior, and a notable reduction in the number of neurons in the olfactory bulb. However, inhalation of Citri Reticulata Pericarpium Viride essential oil reversed these effects, improving the olfactory function, neuro-stimulating effect, alleviating anxiety-like behavior, and regulating theta (4-12Hz) oscillation in the hippocampus DG area. These effects were associated with changes in the expression levels of glutamate receptor NMDAR and NeuN in olfactory bulb. Conclusions The study revealed that mice with anxiety induced by chronic restraint stress exhibited significant olfactory dysfunction, providing strong evidence for the causal relationship between anxiety disorders and olfactory dysfunction. Moreover, QP essential oil has the potential to be developed as a therapeutic drug for anxiety disorders, in addition to its role as a complementary anxiolytic.
研究领域:
药理学
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神经科学
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民族药理学
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行为科学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
SCHIZOPHRENIA BULLETIN
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2025
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IF 4.8
Fan Rui,Pu Jianlin,Zhang Jin,Yu Minglan,Wang Tingting,Geng Xiaoqi,Dong Wei,Ma Rong,Wang Binglong,Wu Jianfei,Liu Kezhi,Hashimoto Kenji,Xiang Bo
BackgroundSocial withdrawal is a core symptom of schizophrenia (SCZ), yet its underlying molecular mechanisms remain unclear. Gα13 (GNA13), a G protein alpha subunit, has been implicated in SCZ susceptibility. This study investigated the role of Gα13 in social behavior by overexpressing it in the medial prefrontal cortex (mPFC) pyramidal neurons of mice.Study DesignIn this study, we first constructed CRE recombinase overexpressing Gα13 gene mice using CRISPR/Cas9 technology, tested the social behaviors by three-box socialization test, detected the changes of neuronal activities during social activities in mice by calcium signal fiber-optic recordings, observed the changes of dendritic spines by Golgi staining, applied RNA sequencing (RNA-Seq) to find the relevant targets, and observed whether it could reverse the abnormalities by pharmacological experiments social behavior. The electrophysiological characteristics of Gα13 overexpression were investigated using the whole-cell membrane clamp technique, followed by assessment of the severity of SCZ patients and social withdrawal using the PANSS scale and measurement of human plasma Gα13 protein levels using the ELISA technique, and the clinical correlation between the two was assessed.Study ResultsGα13 overexpression (Gα13-OE) mice exhibited significant social deficits in the three-chamber test, showing reduced sociability but normal social novelty recognition. Fiber photometry recordings revealed decreased neuronal activity during social interactions, and Golgi staining showed reduced dendritic spine density in mPFC pyramidal neurons. RNA-Seq identified downregulation of Adcyap1, affecting the cAMP/PKA signaling pathway and NMDA receptor (NMDAR) function. Pharmacological activation of Adcyap1 with PACAP-38 or NMDAR with D-cycloserine rescued the social deficits and restored synaptic function. Conversely, knockdown of Gα13 in an MK-801-induced SCZ mouse model ameliorated social behavior abnormalities. Clinically, patients with SCZ exhibited elevated plasma levels of Gα13, which positively correlated with the severity of social withdrawal symptoms measured by the PANSS G16 item.ConclusionsThese findings suggest that overexpression of Gα13 in the mPFC impairs social behavior by disrupting neuronal function and synaptic plasticity via the Adcyap1/cAMP/PKA/NMDAR pathway. Targeting Gα13 may offer a novel therapeutic strategy for addressing social deficits in SCZ.
研究领域:
神经生物学
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精神病学
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分子神经科学
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信号转导
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行为神经科学
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转化医学
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突触生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2024
·
IF 4.8
Rong-Xin Song,Xiao-Yi Ma,Ting-Ting Zhou,Zhi-Fang Yu,Jun Wang,Bao-Dong Li,Yu-Mo Jing,Han Wang,Yue Fu,Rui-Zhao Lv,Shi-Yan Jia,Xiao-Ming Li,Li-Min Zhang
Objective Hemorrhagic shock and resuscitation (HSR) cause inflammatory responses in the gastrointestinal tract and is associated with substantial morbidity and mortality rates. Hydrogen sulfide (H 2 S), a gasotransmitter with pleiotropic activity, exhibits anti-inflammatory benefits at physiological levels. However, deleterious effects are observed when its concentration increases. In this investigation, we employed a mouse model of HSR to examine the effects of an H 2 S scavenger on the gastrointestinal tract and brain, with emphasis on N-Methyl- d -Aspartate (NMDA) receptor function. Methods Mice were immediately administered dl -propargylglycine (PAG) intragastrically as an H 2 S scavenger after HSR exposure. The O-maze and buried beads tests were used to assess compulsive- and anxiety-like behaviors. Pathological changes in the intestine were evaluated at 24 and 30 days after HSR. Subsequently, at 30 days after HSR, we examined electrophysiological and pathological changes in the amygdala. Results Within 24 h of HSR exposure, animals treated with PAG showed significantly lower colonic injury. Additionally, compared to the HSR-treated mice 30 days after HSR, the PAG-treated mice displayed reduced buried beads, increased open-arm time, lower blood levels of Diamine Oxidase (DAO) and considerably improved ZO-1 intensity, a stronger association between the delta rhythm phase and beta activity amplitude, and lower neuroinflammatory response in the amygdala. MK-801, an NMDA receptor inhibitor, significantly reversed H 2 S-induced intestinal and cerebral injury. Conclusion This experimental data suggests that H 2 S-induced excessive activation of NMDA receptors contributes to anxiety- and compulsive-like behaviors caused by HSR.
研究领域:
神经科学
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药理学
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病理生理学
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行为科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）