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TRPV4 Regulates Soman-Induced Status Epilepticus and Secondary Brain Injury via NMDA receptor and NLRP3 Inflammasome

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Neuroscience Bulletin 2021年第7期37卷 905-920页

作者： Shuai Wang Huanhuan He Jianhai Long Xin Sui Jun Yang Guodong Lin Qian Wang Yongan Wang Yuan Luo State Key Laboratory of Toxicology and Medical Countermeasures Institute of Pharmacology and ToxicologyAcademy of Military Medical SciencesBeijing 100850China

Nerve agents are used in civil wars and terrorist attacks,posing a threat to public safety.Acute exposure to nerve agents such as soman(GD)causes serious brain damage,leading to death due to intense seizures induced by acetylcholinesterase inhibition and neuronal injury resulting from increased excitatory amino-acid levels and neuroinflammation.However,data on the anticonvulsant and neuroprotective efficacies of currently-used countermeasures are limited.Here,we evaluated the potential effects of transient receptor vanilloid 4(TRPV4)in the treatment of soman-induced status epilepticus(SE)and secondary brain injury.We demonstrated that TRPV4 expression was markedly up-regulated in rat hippocampus after soman-induced seizures.Administration of the TRPV4 antagonist GSK2193874 prior to soman exposure significantly decreased the mortality rate in rats and reduced SE intensity.TRPV4-knockout mice also showed lower incidence of seizures and higher survival rates than wild-type mice following soman exposure.Further in vivo and in vitro experiments demonstrated that blocking TRPV4 prevented NMDA receptor-mediated glutamate excitotoxicity.The protein levels of the NLRP3 inflammasome complex and its downstream cytokines IL-1βand IL-18 increased in soman-exposed rat hippocampus.However,TRPV4 inhibition or deletion markedly reversed the activation of the NLRP3 inflammasome pathway.In conclusion,our study suggests that the blockade of TRPV4 protects against soman exposure and reduces brain injury following SE by decreasing NMDA receptor-mediated excitotoxicity and NLRP3-mediated neuroinflammation.To our knowledge,this is the first study regarding the“dual-switch”function of TRPV4 in the treatment of soman intoxication.

关键词： Nerve agents Soman TRPV4 NMDA receptor NLRP3 inflammasome

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Effects of ketamine-midazolam anesthesia on the expression of nmda and AMPA receptor subunit in the peri-infarction of rat brain

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Chinese Medical Journal 2006年第18期119卷 1555-1562页

作者： ZHANG Yue-lin ZHANG Peng-bo QIU Shu-dong LI Yong TIAN Ying-fang WANG Ying Department of Neuroantomy and Histology Embryology School of Medicine Xi＇an Jiaotong University Xi＇an 710061 China Department of Neurosurgery Shaanxi Provincial People＇s Hospital Xi＇an 710068 China Department of Anesthesiology Second Affiliated Hospital School of Medicine Xi＇an Jiaotong University Xi＇an 710004 China

Background Activation of N-methyl-D-aspartate （nmda） receptors and alpha-amino-3-hydroxy-5-methyl- 4-isoxazole-propionic acid （AMPA） receptors play an important role in the neurons death induced by ischemia. The mitigating effect of intravenous anesthetics on ischemic neuron injury is related to their influence on NMDA receptors. This study was performed to investigate the effect of ketamine-midazolam anesthesia on the nmda and AMPA receptor subunits expression in the peri-infarction of ischemic rat brain and explore its potential mechanism of neuroprotection. Methods Thirty Sprague Dawley （SD） rats were subjected to permanent middle cerebral artery occlusion under ketamine/atropine （100/0.05 mg/kg） or ketamine-midazolam/atropine （60/50/0.05 mg/kg） intraperitoneal anesthesia （n=15 each）. Twenty-four hours after ischemia, five rats in each group were killed by injecting the above dosage of ketamine or ketamine-midazolam intraperitoneally and infarct size was measured. Twenty-four and 72 hours after ischemia, four rats in each group were killed by injecting the above dosage of ketamine or ketamine-midazolam intraperitoneally. After staining the brain tissue slices with toluidine blue, the survived neurons in the peri-infarction were observed. Also, the expression level of NMDA receptors 1 （NR1）, NMDA receptors 2A （NR2A）, NMDA receptors 2B （NR2B） and AMPA （GluR1 subunit） were determined by grayscale analysis in immunohistochemical stained slices. Results Compared with ketamine anesthesia, ketamine-midazolam anesthesia produced not only smaller infarct size [（24.1±4.6）% vs （38.4±4.2）%, P〈0.05], but also higher neuron density （24 hours： 846±16 vs 756±24, P〈0.05; 72 hours： 882±22 vs 785± 18, P〈0.05） and lower NR2A （24 hours： 123.0±4.9 vs 95.0±2.5, P〈 0.05; 72 hours： 77.8±4.1 vs 54.2±3.9, P〈0.05） and NR2B （24 hours： 98.5±2.7 vs 76.3±2.4, P〈0.05; 72 hours： 67.2±7.5 vs 22.2± 2.6, P〈0.05） expression level in the peri-infarction following ischemia. Conclusion The protective effects of ketamine-midazolam anesthesia o

关键词： ketamine midazolam cerebral ischemia NMDA receptor AMPA receptor

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An NMDA receptor and NO cascades dependent presynaptic LTP at glutamatergic synapses of the PVN magnocellular neurosecretory cells in vitro in rats

An NMDA receptor and NO cascades dependent presynaptic LTP a...

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2019中国生理学会学术年会暨张锡钧基金第十五届全国青...

作者： Bing-Xue LI Bin-Bin ZHANG Hua JIN De-Lai QIU Chun-Ping CHU Brain Science Research Center Yanbian University Yanbian University Hospital Yanbian University

Objective The magnocellular neurosecretory cells（MNCs） of the hypothalamic paraventricular nucleus（PVN） integrate incoming signals to secrete oxytocin（OT） and vasopressin（VP） from their nerve terminals in the posterior pituitary gland.It has been demonstrated that high frequency stimulation（HFS） of afferent fibers induced an NMDA receptor-dependent LTP of excitatory glutamatergic inputs in the supraoptic nucleus（SON） MNCs of rat hypothalamic slices,therefore, the N-methyl-D-aspartic acid（nmda） receptors-dependent plasticity in PVN MNCs may be involved in nitric oxide（NO） production and PKA signaling pathway.However, the NO and PKA signaling cascades in the long-term plasticity in PVN MNCs is currently unknown.Methods we used whole-cell patch-clamp recording, single-cell reverse transcription-multiplex polymerase chain reaction（SC-RT-mPCR）, biocytin histochemistry and pharmacological methods to examine the mechanism of high frequency stimulus（HFS, 100 Hz）-induced long-term potentiation（LTP） at glutamatergic synapses in the PVN MNCs of juvenile male rats.Results HFS-induced LTP at glutamatergic synapses was accompanied by a decrease in the paired-pulse ratio（PPR） of the PVN MNCs.In these MNCs, HFS-induced LTP persisted in the presence of a group 1 metabotropic glutamate receptor（mGluR1） antagonist;however, it was abolished by an NMDA receptor blocker.Notably, HFS-induced LTP in the PVN MNCs was completely prevented by a nitric oxide synthase（NOS） inhibitor.The application of an NO donor not only induced the LTP of excitatory glutamatergic inputs in the PVN MNCs, but also occluded the HFS-induced LTP in these MNCs.Moreover, HFS-induced LTP in the PVN MNCs was also abolished by a specific protein kinase A（PKA） inhibitor, KT5720.Conclusion Our results indicate that a HFS can induce an NMDA receptor and NO cascades dependent on presynaptic glutamatergic LTP in the PVN MNCs via a PKA signaling pathway.

关键词： hypothalamic paraventricular nucleus（PVN） long-term synaptic plasticity NMDA receptor nitric oxide whole-cell recording protein kinase A

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Spider venom peptides targeting on a novel α2δ-1–NMDA receptor coupling in neuropathic pain

Spider venom peptides targeting on a novel α2δ-1–NMDA rec...

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中国生物化学与分子生物学会第十二届全国会员代表大会暨2...

作者： Yiying Ding Shengmei Yang Fang Qu Hui-Lin Pan Jinjun Chen College of Bioscience and Biotechnology Hunan Agricultural University

Spiders are traditional medicine used for the treatment of chronic pain,but the molecular mechanism involved is not clear.Spiders use their venom to rapidly paralyze their prey through targeting their prey’s nervous system efficiently and specifically.Studying spider toxin peptides has received much attention in the pain field in recent years.However,previous work is mainly focused on the pore-forming subunits of the channels,which often produce intolerable side effects.α2δ-1 was previously considered as a subunit of voltage-gated calcium channels and is up-regulated in primary sensory neurons and spinal cord dorsal horn neurons in peripheral nerve injury-induced chronic pain.α2δ-1 is also the target of gabapentin and pregabalin,which are commonly used analgesics for treating neuropathic pain.We identified that a novel α2δ-1–NMDA receptor coupling is critically involved in neuropathic pain and gabapentin action.We study the spider venom peptides targeting on α2δ-1 by using membrane system yeast two-hybrid and pull-down,dual high-throughput screening,which can then be applied to study the functions in the cells and animal models to determine their molecular mechanisms in treating neuropathic pain.We put forward an innovative project to study the molecular basis of spider toxins pertinent to their analgesic effects,based on the studies of spider venom peptidomics and the mechanism of α2δ-1 in neuropathic pain by our team.The present study is expected to discover new research tools that can be used for studying the mechanism of acute and chronic pain and may develop novel drug leads for treating various painful conditions.

关键词： Spider venom Neuropathic pain Accessory subunit CACNA2D1 NMDA receptor

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ASIC1a regulates ventral hippocampal-infralimbic prefrontal plasticity and fear extinction via BDNF-NMDA receptor signaling

ASIC1a regulates ventral hippocampal-infralimbic prefrontal ...

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长三角地区神经科学论坛2017

作者： Qin Wang Xing-Lei Song Qin Jiang Qi Wang Yan-Jiao Wu Wei-Guang Li Tian-Le Xu Collaborative Innovation Center for Brain Science Department of Anatomy and Physiology Shanghai Jiao Tong University School of Medicine

Fear extinction is associated with dynamic changes in neuronal activity and connectivity within fear circuits,mainly including hippocampus,medial prefrontal cortex（m PFC）,and amygdala.However,it is still unclear how this extinction-related plasticity is implemented at the molecular and circuit level.Acid-sensing ion channel 1a（ASIC1a）,a member of the degenerin/epithelial Na+channel family,has been reported play an important role in synaptic plasticity and learning and memory,such as fear learning.Here,we identify a critical role of ASIC1a in ventral hippocampus（v HPC）-infralimbic（IL）cortex pathway for fear extinction.We found mice with ASIC1a deletion in v HPC by Cre/lox recombination（ASIC1ac KO）,si RNA or ASIC1a inhibition by Pc TX-1 showed impaired fear extinction,while overexpression of ASIC1a in v HPC facilitated fear extinction in wild type mice.To explore the mechanisms,we did whole-transcriptome analysis with RNA sequencing,and showed that bdnf gene is a likely key molecular substrate recruited by ASIC1ato influence fear extinction.Supporting this possibility,Extinction learning induced significant BDNF upregulation in v HPC,which is compromised in ASIC1ac KO mice.Moreover,overexpression of BDNF in v HPC restored the deficiency of fear extinction in ASIC1ac KO mice.By combining optogeneticswithacute slice electrophysiology,we showed that fear extinction learning enhanced excitatory synaptic transmission in the v HPC-IL projection,characterized as the enhanced nmdaR/AMPAR ratio,whichwas severely impaired in ASIC1ac KO mice,and then could be rescued by simultaneous addition of BDNF.Thein-site delivery of BDNF protein to IL also could reverse the impairment of fear extinction induced by v HPCASIC1a deletion.In addition,the similar genetic and pharmacological manipulations of ASIC1a in the IL didn’t have any effect on fear extinction.Together,these results collectively establish a novel molecular pathway involving ASIC1a and BDNF-NMDA receptor signaling specifically in the v HPC-IL circuit that is critical for

关键词： Fear extinction ASIC1a ventral hippocampus infralimbic prefrontal cortex BDNF NMDA receptor

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The Effects of Alcohol-Sensitive Positions in the Third Membrane-associated Domains of the GluN1 and GluN2A Subunits on NMDA receptor Expression

The Effects of Alcohol-Sensitive Positions in the Third Memb...

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中国神经科学学会第十二届全国学术会议

作者： Shan Zhou Hong Ren Union Hospital Tongji Medical College Huazhong University of Science and Technology

The N-methyl-D-aspartate（nmda） receptor, a subtype of ionotropic glutamate receptor,is an important target of alcohol action in the central nervous system. Acute alcohol exposure inhibits NMDA receptor currents and Ca2+ influx in various brain regions. In contrast, chronic alcohol exposure results in a compensatory increase in the NMDA receptor binding density, m RNA and protein expression of NMDA receptor subunits. However, the molecular mechanism of alcohol-induced changes in NMDA receptor function is still not fully elucidated. Previous studies have found multiple acute alcohol-sensitive amino acid residue sites in the third（M3） and fourth（M4） transmembrane-associated domains of the NMDA receptor. In this study, the effects of alcohol-sensitive amino acid residues in the third membrane-associated domains of the Glu N1 and Glu N2 A subunits on the NMDA receptor expression were experimented by using site-directed mutagenesis, transiently-transfected HEK293 T cells, and western blot. As a result, tryptophan or alanine substitution at Glu N1（G638） or Glu N1（F639） significantly influence the NMDA receptor expression（p＜0.05）. This also does for tryptophan substitution at Glu N2 a（F636）, however, alanine substitution at Glu N2 A（F636） does not（p＞0.05）.This finding indicates the alcohol-sensitive amino acid residues on M3 which not only regulate the sensitivity of acute alcohol and the electrophysiological properties of ion channels, but also play an important role in receptor expression.

关键词： NMDA receptor alcohol expression

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The Effect of Coriaria Lactone on NMDA receptor Mediated Currents in Rat Hippocampal CA1 Neurons

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2000年第1期20卷 6-9页

作者：庞志平王殿仕郝建东朱长庚王阿敬李继硕 Department of Anatomy The Fourth Military Medical University Xi’an Department of Anatomy School of Basic Medical Sciences Tongji Medical University Wuhan Department of Anatomy Research Center of Experimental Medicine Tongji Medical University Wuhan

Summary: To investigate the exact mechanism of epileptogenesis induced by coriaria lactone (CL), the effect of CL on NMDA receptor mediated current (IAsp) in rat hippocampal CA1 neu- rons was investigated by using nystatin perforated whole-cell patch clamp. 10-6-10-4 mol/L Asp acted on NMDA receptors and elicited an inward current (IAsp) at a holding potential (VH) of -40 mV in presence of 10-6 mol/L glycine and absence of Mg2+ extracellularly. CL enhanced NMDA receptor mediated current induced by Asp, but had no effect on threshold concentration, EC50, Hill coefficient as well as maximal-effect concentration and reversal potential of IAsp. The effect had no relationship with holding potential. These results showed that CL could enhance NMDA receptor mediated current to increase [Ca2+]i of neurons by acting on Gly site, thereby inducing epilepsy.

关键词： coriaria lactone NMDA receptor nystatin perforated whole-cell patch clamp hippocampal CA1 neurons

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Diabetes changes the expression of NMDA receptor subunits in the mouse retina

Diabetes changes the expression of NMDA receptor subunits in...

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中国生理学会第24届全国会员代表大会暨生理学学术大会

作者：王璐翁史钧钟咏梅杨雄里上海复旦大学神经生物学研究所

Diabetic retinopathy（DR）,one of the common complications of diabetes,is a leading cause of vision impairment and blindness in adults.The N-methyl-D-aspartate（nmda）-type glutamate receptor（nmdaR）-mediated excitotoxicity is thought to contribute to retinal neural cell apoptosis and dysfunction in this disease.This study aims to investigate whether diabetes induces alterations in the expression levels of nmdaR subunits.Diabetes was induced by intraperitoneal injection of streptozotocin（STZ）in C57BL/6 mice.The protein expression levels of nmdaR subunits were determined by western blotting in mouse retinas 4,8,12,and 16 weeks after the onset of STZ-induced diabetes.In mouse retinas 4 weeks after the onset of STZ-induced diabetes,a significant increase in expression levels of the nmdaR subunits NR2A,NR2B and NR3B was detected,as compared with age-matched controls.In contrast,no changes in protein levels of NR1,NR2C,NR2D and NR3A were observed at this stage.After 8 weeks of diabetes,the levels of NR1 and NR3A were also significantly increased and those of NR2A,NR2B and NR3B were continuously upregulated,but the expression of NR2C and NR2D kept unchanged.At 12 and16 weeks of diabetes,the expression of NR2B,NR3B,NR1 and NR3A was continuously elevated,but there was no statistical difference in levels of NR2A,NR2C and NR2D between diabetic retinas and controls.These results suggest that visual dysfunction as well as retinal cell apoptosis during the early stage of diabetes could be in part due to alterations in the expression of retinal nmda subunits.

关键词： NMDA receptor diabetes retina western blot

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Myosin IIb regulates NMDA receptor trafficking through MLCK-triggered actin reorganization

Myosin IIb regulates NMDA receptor trafficking through MLCK-...

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中国神经科学学会第十届全国学术会议

作者： Yun-Fei Bu Ning Wang Wen Yao Lin-Lin Chen Tian Tian Wei Lu Department of Neurobiology Nanjing Medical University Institute of Life Sciences Southeast University

nmda-type glutamate receptor plays a central role in various brain functions.Precise targeting and localization of NMDA receptor（nmdaR） is critical for proper complement of its function.nmdaR trafficking is tightly controlled in a temporal and spatial manner.However,little is known about the signaling molecules involved in regulation of nmdaR trafficking into postsynaptic density（PSD）.Here,we found Myosin IIb,a motor protein that was previously found in nmda complex at postsynaptic site,is required for PKC-induced nmdaR trafficking and synaptic localization.Inhibiting Myosin IIb function with either Myosin IIb knockdown or pharmacological treatments that inhibit motor activity remarkably blocked nmdaR trafficking elicited by protein kinase C（PKC） activation.We further demonstrated that myosin light chain kinase（MLCK） could act as a PKC downstream mediator to phosphorylate myosin Ⅱ light chain（MLC） and subsequently promote nmdaR trafficking by reorganizing actin structure.Importantly,we detected similar effects by MLCK and actin reorganization in nmdaR trafficking model induced by physiological theta burst stimulation（TBS）.We conclude that myosin IIb can take an important role in nmdaR trafficking through MLCK-triggered actin reorganization.

关键词： PKC NMDA receptor trafficking MLCK LTP

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NMDA receptor-activation in CA1 pyramidal cells involved in hippo-campal spontaneous oscillations

NMDA receptor-activation in CA1 pyramidal cells involved in ...

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中国神经科学学会第十届全国学术会议

作者： Yu-Zhang LIU Zhiru WANG Laboratory of Sensory Plasticity Key Laboratory of Brain Functional GenomicsMinistry of EducationEast China Normal University

Objective Spontaneous oscillations in the hippocampus are believed to be critical for memory consolidation,a process that results from activity-dependent neuronal plasticity in this circuit.NMDA receptors have been shown to play important in neuronal plasticity.However,whether the involvement of this receptor in spontaneous activity in the in vivo hippocampus is the possible contribution to memory consolidation remains unclear.Method In vivo whole-cell patch-clamp recordings were performed from hippocampal CA1 pyramidal cells on anaesthetized rats to measure membrane-potential（MP） changes occurring spontaneously.Results We found that intracellularly blocking NMDA receptors by MK801 resulted in a significant reduction in the amplitude of spontaneous MP oscillations.Likewise,when cells were held-80 mV,the spontaneously occurring MP oscillations were largely reduced,and no further reduction effects could be observed by intracellularly treating cells with MK801.Conclusion Our results showed that hippocampal oscillations consist of a large amount of NMDA receptors that are continuously activated,which may serve as an important mechanism for hippocampal memory consolidation.

关键词： NMDA receptor hippocampus oscillation memory consolidation

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