AIP Advances
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2024
·Vol. 14
·期 8
·
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
·
医学
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产品关联
DOI
高影响因子
Cell Death & Disease
·
2018
·Vol. 9
·期 8
·1-20
·
IF 5.638
Yang Qin,Zheng Fangshuo,Hu Yida,Yang Yi,Li Yun,Chen Guojun,Wang Wei,He Miaoqing,Zhou Ruijiao,Ma Yuanlin,Xu Demei,Tian Xin,Gao Xiaoya,Wang Qing,Wang Xuefeng
Epilepsy is one of the most prevalent and drug-refractory neurological disorders. Zinc finger DHHC-type containing 8 (ZDHHC8) is a putative palmitoyltransferase that is highly expressed in the brain. However, the impact of ZDHHC8 on seizures remains unclear. We aimed to explore the association of ZDHHC8 with epilepsy and investigate its in epileptogenesis in in vivo and in vitro models through behavioral, electrophysiological, and pathological studies. We used kainic acid- and pilocarpine-induced C57BL/6 mice and magnesium-free-induced pyramidal neurons as experimental epileptic models in this study. We first found increased ZDHHC8 expression in the brains of temporal lobe epilepsy (TLE) patients, similar to that observed in chronic epileptic mice, strongly suggesting that ZDHHC8 is correlated with human epilepsy. In the in vitro seizure models, knocking down ZDHHC8 using recombinant adeno-associated virus (rAAV) delayed seizure precipitation and decreased chronic spontaneous recurrent seizures (SRSs) and epileptiform-like discharges, while ZDHHC8 overexpression had the opposite effect. ZDHHC8 levels were consistent with seizure susceptibility in induced mice with SRSs. In an in vitro magnesium-free model, neuronal hyperexcitability and hypersynchrony were reduced in ZDHHC8-knockdown neurons but were increased in ZDHHC8-overexpressing neurons. To further explore the potential mechanisms, we observed that ZDHHC8 had a significant modulatory effect on 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid (AMPA) receptor-related excitatory, but not inhibitory, glutamatergic synaptic neurotransmission, further affecting the inward rectification of AMPA currents in acute hippocampal slices in whole-cell recordings. ZDHHC8 facilitated GluA1 trafficking to the neuronal surface in the hippocampus, as shown by immunoprecipitation and Western blotting. These results suggest that ZDHHC8 may promote the generation and propagation of seizures in humans and that knocking down ZDHHC8 might produce anti-epileptogenic effects in drug-resistant epilepsy. Our study provides evidence that may facilitate the development of an alternative approach for the treatment of epilepsy by modulating AMPA/GluA1-mediated neurotransmission.
研究领域:
神经科学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
EMBO REPORTS
·
2022
·Vol. 23
·期 10
·e54543
·
IF 9.071
Xuanyue Ma,Liuren Li,Ziming Li,Zhengyi Huang,Yaorong Yang,Peng Liu,Daji Guo,Yueyao Li,Tianying Wu,Ruixiang Luo,Junyu Xu,Wen-Cai Ye,Bin Jiang,Lei Shi
Regulation of mRNA translation is essential for brain development and function. Translation elongation factor eEF2 acts as a molecular hub orchestrating various synaptic signals to protein synthesis control and participates in hippocampus-dependent cognitive functions. However, whether eEF2 regulates other behaviors in different brain regions has been unknown. Here, we construct a line of Eef2 heterozygous (HET) mice, which show a reduction in eEF2 and protein synthesis mainly in excitatory neurons of the prefrontal cortex. The mice also show lower spine density, reduced excitability, and AMPAR-mediated synaptic transmission in pyramidal neurons of the medial prefrontal cortex (mPFC). While HET mice exhibit normal learning and memory, they show defective social behavior and elevated anxiety. Knockdown of Eef2 in excitatory neurons of the mPFC specifically is sufficient to impair social novelty preference. Either chemogenetic activation of excitatory neurons in the mPFC or mPFC local infusion of the AMPAR potentiator PF-4778574 corrects the social novelty deficit of HET mice. Collectively, we identify a novel role for eEF2 in promoting prefrontal AMPAR-mediated synaptic transmission underlying social novelty behavior.
研究领域:
神经科学
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分子生物学
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行为科学
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DOI
PubMed
高影响因子
Molecular Medicine Reports
·
2014
·Vol. 10
·期 1
·248-254
·
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
NEUROENDOCRINOLOGY
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2024
·
IF 3.2
Zhang Jiaxian,Lai Wanlin,Tang Yusha,Gao Jing,Zhou Xiangyang,Chen Lei
Introduction:
In women of childbearing age with epilepsy, 40% experience the comorbidity of polycystic ovary syndrome (PCOS), which is marked by a higher prevalence of hyperandrogenism. Our recent clinical observations indicate the potential contribution of hyperandrogenism-induced PCOS to epilepsy susceptibility, and this study aimed to unravel the underlying factors that increase the susceptibility of females to epilepsy. Methods:
A letrozole-induced PCOS rat model was employed to simulate endogenous hyperandrogenism. Susceptibility was assessed through seizure kindling rates using pentetrazol and electroencephalogram recordings. Additionally, the role of androgens in epilepsy was verified through interventions using Diane-35. Results:
This study revealed that letrozole induced elevated testosterone levels and PCOS-related changes in female rats. PCOS rats, through pentetrazol-kindling, exhibited a reduced seizure threshold compared with controls. Elevated testosterone levels were observed in both the hippocampal and frontal brain tissues, accompanied by changes in circulation. Two weeks of Diane-35 intervention showed a tendency to alleviate these changes, modifying testosterone levels in both the plasma and brain tissue. Western blotting and immunohistochemistry revealed increased expression of GABA-A receptor in the hippocampus and decreased AMPA receptor expression in the frontal cortex, correlating with anti-epileptic status in PCOS rats. Conclusion:
This study delves into the impact of elevated androgen levels on seizure threshold, providing crucial insights into the underpinnings of the comorbidity between PCOS and epilepsy. These findings significantly contribute to the evolving field of epilepsy research, emphasizing the imperative consideration of hormonal influences for the development of targeted therapeutic interventions in individuals with epilepsy and PCOS
研究领域:
神经科学
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内分泌学
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癫痫研究
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生殖医学
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DOI
PubMed
高影响因子
NEUROCHEMICAL RESEARCH
·
2016
·Vol. 41
·期 11
·2890-2903
·
IF 2.472
Han Jun,Zhang Hai,Wang Sheng,Zhou Jun,Luo Yi,Long Li-Hong,Hu Zhuang-Li,Wang Fang,Chen Jian-Guo,Wu Peng-Fei
Sulfhydryl compounds such as dithiothreitol (DTT) and β-mercaptoethanol (β-ME) are widely used as redox agents. Previous studies in our group and other laboratory have reported the effect of sulfhydryl compounds on the function of glutamate receptor, including plasticity. Most of these findings have focused on the N -methyl- d -aspartic acid receptor, in contrast, very little is known about the effect of sulfhydryl compounds on α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR). Here, we observed that DTT (100 μM), β-ME (200 μM) and l -cysteine (200 μM) significantly elevated the surface expression of AMPARs via reducing their palmitoylation in rat hippocampal slices in vitro . Increased surface stability of AMPARs was not be correlated with the altered redox status, because the chemical entities containing mercapto group such as penicillamine (200 μM) and 2-mercapto-1-methylimidazole (200 μM) exhibited little effects on the surface expression of AMPARs. Computing results of Asp-His-His-Cys (DHHC) 3, the main enzyme for palmitoylation of AMPARs, indicated that only the alkyl mercaptans with chain-like configuration, such as DTT and β-ME, can enter the pocket of DHHC3 and disrupt the catalytic activity via inhibiting DHHC3 auto-palmitoylation. Collectively, our findings indicate a novel redox-independent mechanism underlay the multiple effects of thiol reductants on synaptic function.
研究领域:
神经科学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
EMBO REPORTS
·
2023
·
IF 7.7
Zhi-Jun Zhang,Han-Yu Shao,Chuan Liu,Hao-Lin Song,Xiao-Bo Wu,De-Li Cao,Meixuan Zhu,Yuan-Yuan Fu,Juan Wang,Yong-Jing Gao
A11 dopaminergic neurons regulate somatosensory transduction by projecting from the diencephalon to the spinal cord, but the function of this descending projection in itch remained elusive. Here, we report that dopaminergic projection neurons from the A11 nucleus to the spinal dorsal horn (dopaminergicA11-SDH) are activated by pruritogens. Inhibition of these neurons alleviates itch-induced scratching behaviors. Furthermore, chemogenetic inhibition of spinal dopamine receptor D1-expressing (DRD1+) neurons decreases acute or chronic itch-induced scratching. Mechanistically, spinal DRD1+ neurons are excitatory and mostly co-localize with gastrin-releasing peptide (GRP), an endogenous neuropeptide for itch. In addition, DRD1+ neurons form synapses with GRP receptor-expressing (GRPR+) neurons and activate these neurons via AMPA receptor (AMPAR). Finally, spontaneous itch and enhanced acute itch induced by activating spinal DRD1+ neurons are relieved by antagonists against AMPAR and GRPR. Thus, the descending dopaminergic pathway facilitates spinal itch transmission via activating DRD1+ neurons and releasing glutamate and GRP, which directly augments GRPR signaling. Interruption of this descending pathway may be used to treat chronic itch.
研究领域:
神经科学
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药理学
·
疼痛研究
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产品关联
DOI
PubMed
高影响因子
Neural Regeneration Research
·
2023
·Vol. 18
·期 10
·2315
·
IF 6.1
Duan Tian-Qi,Gao Zhao-Lin,Luo Ai-Xiang,Chen Dan,Tong Jian-Bin,Huang Ju-Fang
Adipose mesenchymal stem cells (ADSCs) have protective effects against glutamate -induced excitotoxicity , but ADSCs are limited in use for treatment of optic nerve injury. Studies have shown that the extracellular vesicles (EVs) secreted by ADSCs (ADSC-EVs) not only have the function of ADSCs, but also have unique advantages including non-immunogenicity, low probability of abnormal growth, and easy access to target cells. In the present study, we showed that intravitreal injection of ADSC-EVs substantially reduced glutamate -induced damage to retinal morphology and electroretinography . In addition, R28 cell pretreatment with ADSC-EVs before injury inhibited glutamate -induced overload of intracellular calcium, downregulation of α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptor (AMPAR) subunit GluA2 , and phosphorylation of GluA2 and protein kinase C alpha in vitro . A protein kinase C alpha agonist, 12-O-tetradecanoylphorbol 13-acetate, inhibited the neuroprotective effects of ADSC-EVs on glutamate -induced R28 cells . These findings suggest that ADSC-EVs ameliorate glutamate -induced excitotoxicity in the retina through inhibiting protein kinase C alpha activation.
研究领域:
神经科学
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细胞生物学
·
眼科学
·
干细胞研究
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产品关联
DOI
PubMed
高影响因子
Oncotarget
·
2017
·
IF 5.168
Qin Yang,Yi-Da Hu,Xue-Feng Wang,Fang-Shuo Zheng
Epilepsy is the most prevalent chronic neurological disorder, and its pathological mechanism indicates that an imbalance between excitatory and inhibitory neurotransmission leads to neuronal hyperexcitability. Previous studies have suggested that dl-3n-butylphthalide (NBP) regulates the excitatory neurotransmitter glutamate in the brains of epileptic mice, however, the mechanisms are unknown. We investigated behavioral and electrophysiological factors in rats using NBP. In an in vivo pentylenetetrazole (PTZ)-induced epileptic seizure animal model, NBP decreased the generalized tonic-clonic seizure (GTCS) severity. In an acute hippocampal slice 4-aminopyridine (4-AP) epilepsy model in vitro , NBP decreased the epileptiform activity and miniature excitatory postsynaptic current (mEPSC) amplitude; there was no change in the miniature inhibitory postsynaptic current (mIPSC) amplitude or frequency. This effect suggested changes in excitatory synaptic transmission, which was altered through postsynaptic GluA2-lacking calcium-permeable AMPA receptors (CP-AMPARs). These findings showed that NBP suppressed epileptiform activity in these epilepsy models and provided the first detailed electrophysiological analysis of the impact of NBP in epilepsy models, which may be employed in future experimental or clinical therapies for patients with epilepsy.
研究领域:
神经科学
·
药理学
·
电生理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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