Temporal lobe epilepsy(TLE) is a common type of epilepsy and is not well controlled by current treatments.The frequent failure to treat TLE may be due to our lack of precise cellular/circuit mechanisms underlying TLE....Temporal lobe epilepsy(TLE) is a common type of epilepsy and is not well controlled by current treatments.The frequent failure to treat TLE may be due to our lack of precise cellular/circuit mechanisms underlying TLE.The early series of our studies have proved the success of low-frequency stimulation treatment for epilepsy,which was mainly depending on the stimulation target,the stimulation frequency and stimulation time(the therapeutic-window phenomenon).Now,by using optogenetics,viral tracing,multiple-channel EEG analysis,imaging,electrophysiology and pharmacology strategies,we are continued to investigate the circuit mechanism of therapeutic deep brain stimulation,and found that entorhinal principal neurons mediate antiepileptic ″ glutamatergic-GABAergic″ neuronal circuit for brain stimulation treatments of epilepsy.Meanwhile,we are currently focusing on the interplay of inhibitory and excitatory network in the key input/output regions of the hippocampus that related to the generation of in TLE.Specially,we found that depolarized GABAergic signaling in subicular microcircuit mediates generalized seizures in TLE and a direct septal cholinergic circuit attenuates TLE through driving hippocampal somatostatin inhibition.These findings may be of therapeutic interest in understanding the pathological neuronal circuitry in TLE and further the development of novel therapeutic approaches or drug targets.展开更多
OBJECTIVE To study the function of neuronal nitric oxide synthase(nNOS) in the dentate gyrus(DG) in the pathology of epilepsy.METHODS The expression of nNOS in the DG was measured by qPCR and Western blotting in mice ...OBJECTIVE To study the function of neuronal nitric oxide synthase(nNOS) in the dentate gyrus(DG) in the pathology of epilepsy.METHODS The expression of nNOS in the DG was measured by qPCR and Western blotting in mice 3 and 12 h,1,7,14,and 60 d after treatment with pilocarpine(280 mg·kg-1,ip,one time).We constructed a type of lentiovirus encoding the full length cDNA of nNOS(LV-nNOS-GFP) and injected it and LV-GFP(1 μL) into the DG of the hippocampus 7 d after pilocarpine-induced seizure.The occurrence of epileptic spikes and spontaneous seizure(SRS)were monitored through electroencephalo-graph(EEG) and the protein expression was confirmed by Western blotting.We also constructed a lentioviral vehicle to interfere the expression of nNOS mRNA,which was named as LV-n NOSRNAi-GFP.A volume of 1 μL of LV-nNOS-RNAiGFP or LV-GFP was injected into the DG of the hippocampus 7 d before pilocarpine-induced seizure followed by EEG record and protein detection 2 months later.By EEG,we compared the susceptibility of nNOS knockout and wild-type mice to seizure induction and the development of epilepsy.In addition,we measured the influence of nNOS knockout on the excitability of dentate cells including mEPSC and mIPSC by using patch clamp technique.RESULTS Western blotting and qPCR measurement showed that the mRNA and protein expression of nNOS in the DG was not significantly changed in pilocarpinetreated mice compared with control mice.But the both m RNA and protein expression of nNOS decreased 7,14 and 60 d after treatment with pilocarpine(280 mg·kg-1,ip,one time).With infection of LV-nNOS-GFP in the DG,the decreased level of nNOS was recovered 7 d after seizure induction and the frequency of epileptic spikes and SRS were reversed by nNOS overexpression.We found that nNOS knockout caused a higher susceptive level to seizure induction by pilocarpine.Re-expression of nNOS in the DG of nNOS knockout mice relived the severity of epilepsy.By patch clamp recording,we found that there was no significant difference in the amplitude of mEPSC and mIPSC between nNOS knockout and wild-type mice,but the frequency of mEPSC was increased in nN OS knockout mice.Consistently,knockdown of nNOS by injection of LV-nNOS-RNAi-GFP into the DG caused higher frequency of epileptic spikes and SRS 2 months after pilocarpine-induced seizure.CONCLUSION Neurons expressing nNOS in the DG play an important role in the development of epilepsy.展开更多
OBJECTIVE To examine whether17 AAG and STA9090 have anticonvulsant activity in absence epilepsy.METHODS For the acute seizure study,each group of mice received VPA(dissolved in saline) 100 mg·kg-1,17 AAG(dissolve...OBJECTIVE To examine whether17 AAG and STA9090 have anticonvulsant activity in absence epilepsy.METHODS For the acute seizure study,each group of mice received VPA(dissolved in saline) 100 mg·kg-1,17 AAG(dissolved in 50 μL DMSO) 25 mg·kg-1 or STA9090(dissolved in 20 μL DMSO) 50 mg·kg-1 by oral gavage respectively.The control group received DMSO alone.Thirty minutes after oral gavage,PTZ 80 mg·kg-1 was intraperitoneal injected to induce acute seizures.The number of seizures refers to the total number of epileptic mice after PTZ application.Seizure latency was defined by the time elapsed from PTZ injection to the occurrence of the first seizure.The levels of Hsp90β,GLT-1,GFAP and 20 S proteasome β1 in the cortex and hippocampus were detected by Western blotting.RESULTS The mortality were60% for 17 AAG and 43% for STA9090,and the mortality of valproate group dropped to 20%which decreased by 33.3% compared to model group.Seizure latency of valproate group obviously prolonged compared to model group(P<0.05).But the results demonstrated that 17 AAG and STA9090 had no significant differences in seizure latency.The result of Western blotting has shown that inhibition of Hsp90β significantly reduced expressions of both membrane and cytosolic Hsp90β in the hippocampus and cortex of each group of mice.However,the expressions of GLT-1 and GFAP did not show the significant difference in the cortex and hippocampus.The expression of 20 S proteasome β1 had not been obviously changed in the cortex and hippocampus among the groups.CONCLUSION 17 AAG and STA9090 did not have anticonvulsant activity and did not increase the stability of GLT-1 by disrupting proteasome-dependent GLT-1 degradation in PTZ induced mice of absence epilepsy.展开更多
OBJECTIVE To understand the underlying mechanisms of drug resistant temporal lobe epilepsy(TLE).METHODS In vivo and vitro electrophysiology,optogenetics and chemogenetics were used in a classic multi-drug resistant TL...OBJECTIVE To understand the underlying mechanisms of drug resistant temporal lobe epilepsy(TLE).METHODS In vivo and vitro electrophysiology,optogenetics and chemogenetics were used in a classic multi-drug resistant TLE model.RESULTS Subicular pyramidal neuron activity was not inhibited by the anti-epileptic drug phenytoin in drug resistant rats.This phenomenon was specific to the subiculum,but did not involve surrounding temporal lobe regions.Selective inhibition of subicular pyramidal neurons by both optogenetics and chemogenetics reversed drug resistance.In contrast,selective activation of subicular pyramidal neurons directly induced drug resistance in drug responsive rats.Furthermore,long-term low frequency stimulation at the subiculum,which is clinically feasible,inhibited the activity of subicular pyramidal neurons and reversed drug resistance.CONCLUSION Subicular pyramidal neurons might be a key ″ switch″ mediating drug resistance in TLE and represent a new potential target for more precise treatment of drug resistant TLE.展开更多
OBJECTIVE Temporal lobe epilepsy(TLE)is one of the most common types of human epilepsy,and they are often resistant to current treatments.METHODS By using optogenetic,electrophysiological,imaging and pharmacology stra...OBJECTIVE Temporal lobe epilepsy(TLE)is one of the most common types of human epilepsy,and they are often resistant to current treatments.METHODS By using optogenetic,electrophysiological,imaging and pharmacology strategies,we aimed toinvestigate the underlying circuit mechanism of TLE and tried to developthe novel and efficient approach to control epilepsy.RESULTS(1)Using micro PET and multichannel EEG recording,we found an abnormal neural network,characterized by early hypometabolism and after discharge spread,during the epileptogenensis of TLE.(2)Deep brain stimulation,especially low frequency stimulation,targeted the epileptic focus and the areas outside of the focus(critical regions for seizure spread),such as the piriform cortex,cerebellum,entorhinal cortex or subiculum,reduced seizure severity in TLE.Its anti-epileptic effect is time-window dependent and polarity dependent,which shows a promising strategy for treating epileptic seizures.(3)Using an optogenetic strategy,we demonstrated that excitatory projection from entorhinal cortex to hippocampus instructs the brain-stimulation treatments of epilepsy.(4)Our data from both the clinical and experimental studies further demonstrated that a disinhibitory GABAergic neuronmediated microcircuit in the subiculum contributes to secondary generalized seizures in TLE.(5)Finally,based on abnormal synchronization of the electrical activity in epileptic circuit,we developed electroresponsive hydrogel nanoparticles modified with angiopep-2 to facilitate the delivery of the antiepileptic drug phenytoin sodium,which greatly improves the therapeutic index.CONCLUSION Our findings may update the current view of epileptic neuronal networks and suggest possible promising ways for epilepsy treatment.展开更多
Time:December 6-10,2019Venue:Baltimore Convention Center,Baltimore MD,USA Website:https://meeting.aesnet.org/American Epilepsy Society(AES)2019 Annual Meeting will take place in Baltimore Convention Center,Baltimore M...Time:December 6-10,2019Venue:Baltimore Convention Center,Baltimore MD,USA Website:https://meeting.aesnet.org/American Epilepsy Society(AES)2019 Annual Meeting will take place in Baltimore Convention Center,Baltimore MD,USA on December 6-10,2019.From best practices to breakthrough research,the AES 2019 Annual Meeting offers the most extensive education on everything epilepsy and an unparalleled opportunity to network with the brightest minds in the field.展开更多
Time:December 6-10,2019Venue:Baltimore Convention Center,Baltimore MD,USA Website:https://meeting.aesnet.org/American Epilepsy Society(AES)2019 Annual Meeting will take place in Baltimore Convention Center,Baltimore M...Time:December 6-10,2019Venue:Baltimore Convention Center,Baltimore MD,USA Website:https://meeting.aesnet.org/American Epilepsy Society(AES)2019 Annual Meeting will take place in Baltimore Convention Center,Baltimore MD,USA on December 6-10,2019.From best practices to breakthrough research,the AES 2019 Annual Meeting offers the most extensive education on everything epilepsy and an unparalleled opportunity to network with the brightest minds in the field.展开更多
Time：September 11-15,2016Venue：Prague,Czech RepublicEmail：prague@epilepsycongress.orgWebsite：http：//www.epilepsyprague2016.orgThe 12th European Congress on Epileptology（ECE）will take place in Prague,Czech Repub...Time：September 11-15,2016Venue：Prague,Czech RepublicEmail：prague@epilepsycongress.orgWebsite：http：//www.epilepsyprague2016.orgThe 12th European Congress on Epileptology（ECE）will take place in Prague,Czech Republic on September 11-15,2016.The congress is now a landmark in the epilepsy community agenda and the Prague 2016 promises to be innovative and engaging.展开更多
The input-output relationship of neuronal networks depends heavily on the intrinsic properties of their neuronal elements.Profound changes in intrinsic properties have been observed in various physiological and pathol...The input-output relationship of neuronal networks depends heavily on the intrinsic properties of their neuronal elements.Profound changes in intrinsic properties have been observed in various physiological and pathological processes,such as learning,memory and epilepsy.However,the cellular and molecular mechanisms underlying acquired changes in intrinsic excitability are still not fully understood.Here,we demonstrate that ERG3 channels are critically involved in the regulation of intrinsic excitability in hippocampal CA1 pyramidal neurons and DG granule cells.Knock-down of ERG3 channels significantly increases neuronal intrinsic excitability,which is mainly caused by decreased fast afterhyperpolarization,delayed time to the generation of an action potential and enhanced summation of somatic excitatory post-synaptic potentials.Interestingly,the expression level of ERG3 protein is significantly reduced in human and mouse brain tissues with temporal lobe epilepsy.Moreover,ERG3 channel knock-down in hippocampus significantly enhanced seizure susceptibility,while mice treated with ERG3 channel activator NS1643 were less prone to epileptogenesis.Taken together,our results suggest ERG3 channels play an important role in determining the excitability of hippocampal neurons and dysregulation of these channels may be involved in the generation of epilepsy.ERG3 channels may thus be a novel therapeutic target for the prevention of epilepsy.展开更多
Maternal health in pregnancy:messages from the 2014 UK Confidential Enquiry into Maternal Death妊娠期孕妇保健:2014年英国孕妇死亡机密询问信息New NICE guidance on diagnosing cancer in general practice全科医学癌症诊断新N...Maternal health in pregnancy:messages from the 2014 UK Confidential Enquiry into Maternal Death妊娠期孕妇保健:2014年英国孕妇死亡机密询问信息New NICE guidance on diagnosing cancer in general practice全科医学癌症诊断新NICE指南Can technology help reduce risk of harm in patients with epilepsy?技术是否能够降低癫痫患者伤害风险Support for mothers and their families after life-threatening illness in pregnancy and childbirth:a qualitative study展开更多
OBJECTIVE Temporal lobe epilepsy(TLE) is one of the most common types of human epilepsy,and they are often resistant to current treatments. METHODS By using optogenetic,electrophysiological,imaging and pharmacology st...OBJECTIVE Temporal lobe epilepsy(TLE) is one of the most common types of human epilepsy,and they are often resistant to current treatments. METHODS By using optogenetic,electrophysiological,imaging and pharmacology strategies,we aimed toinvestigate the underlying circuit mechanism of TLE and tried to developthe novel and efficient approach to control epilepsy. RESULTS(1) Deep brain stimulation,especially low frequency stimulation,targeted the epileptic focus and the areas outside of the focus(critical regions for seizure spread),such as entorhinal cortex or subiculum,reduced seizure severity in TLE. Its anti-epileptic effect is time-window dependent and polarity dependent,which shows a promising strategy for treating epileptic seizures.(2) Using an optogenetic strategy,we demonstrated that excitatory projection from entorhinal cortex to hippocampus instructs the brain-stimulation treatments of epilepsy.(3) Our data from both the clinical and experimental studies further demonstrated that a disinhibitory GABAergic neuron-mediated microcircuit in the subiculum contributes to secondary generalized seizures in TLE.(4) Finally,based on abnormal synchronization of the electrical activity in epileptic circuit,we developed electro-responsive hydrogel nanoparticles modified with angiopep-2to facilitate the delivery of the antiepileptic drug phenytoin sodium,which greatly improves the therapeutic index. CONCLUSION Our findings may update the current view of epileptic neuronal networks and suggest possible promising ways for epilepsy treatment.展开更多
2019年10月,罗巍主任医师团队在《运动疾病》(Movement Disorders)发表了其关于家族性皮质肌阵挛性震颤癫痫(FCMTE)的最新研究成果(https://onlinelibrary.wiley.com/doi/abs/10.1002/mds.27832),文章题目为“Intronie(TTTGA)。insertio...2019年10月,罗巍主任医师团队在《运动疾病》(Movement Disorders)发表了其关于家族性皮质肌阵挛性震颤癫痫(FCMTE)的最新研究成果(https://onlinelibrary.wiley.com/doi/abs/10.1002/mds.27832),文章题目为“Intronie(TTTGA)。insertion in SAMD12 also causes familial cortical myoclonice tremor with epilepsy”自2018年6月罗巍主任医师团队鉴定出位于SAMD12基因4号内含子区的(TTTCA)。五核苷酸重复扩增插入为中国FCMTE患者的主要致病突变后,越来越多的报道证实位于不同基因(日本家系中TNRC6A基因,日本和中国家系RAPGEF2基因,泰国家系YEATS2基因)内含子区的(TTTCA)。五核苷酸重复扩增插人为FCMTE的致病突变。在欧洲FCMTE患者中,也发现位于2号染色体和5号染色体上不同基因内含子区的(TTTCA),五核苷酸重复扩增插人致病。上述研究提示FCMTE的致病突变存在(TTTCA)。序列特异性。展开更多
关于收缩压和舒张压的表示方法,经检索相关心血管权威杂志《Circulation》及编辑部讨论,认为先收缩压,后舒张压的表示方法为妥,且首次出现须注明中英文,具体表示方法为,收缩压（SBP）/舒张压（DBP）：120/90 mm Hg。关于Epilepsy的中文...关于收缩压和舒张压的表示方法,经检索相关心血管权威杂志《Circulation》及编辑部讨论,认为先收缩压,后舒张压的表示方法为妥,且首次出现须注明中英文,具体表示方法为,收缩压（SBP）/舒张压（DBP）：120/90 mm Hg。关于Epilepsy的中文翻译应采用＂癫痫＂：根据2013年6月5日国务院公布的《通用规范汉字表》,弃用原全国科技名词审定委员会审定的词＂癫（合成字）＂,采用《通用规范汉字表》中的词＂癫痫＂。展开更多
T1-1 PTPRN mediates endocytosis of NaV1.2 sodium chan⁃nels and suppresses epileptogenesis in mice WANG Yifan1,2*,YANG Hui1,2*,LI Na1,2*,MA Weining3,LIU Shiqi1,2,CHEN Hedan1,2,SONG Huifang1,2,MA Xinyue1,2,YI Jingyun1,2...T1-1 PTPRN mediates endocytosis of NaV1.2 sodium chan⁃nels and suppresses epileptogenesis in mice WANG Yifan1,2*,YANG Hui1,2*,LI Na1,2*,MA Weining3,LIU Shiqi1,2,CHEN Hedan1,2,SONG Huifang1,2,MA Xinyue1,2,YI Jingyun1,2,LIAN Jingjing1,2,TU Xinyu1,2,PENG Chao1,2,HUANG Zhuo1,2(1.State Key Laboratory of Natural and Biomimetic Drugs,Department of Molecular and Cellular Pharmacology,School of Pharmaceutial Sciences,Peking University,Beijing 100191,China;2.IDG/McGovern Institute for Brain Research,Peking University,Beijing 100871,China;3.Department of Neurology,Shengjing Hospital Affiliated to China Medical University,Shenyang 110000,China)Abstract:Epilepsy is a disorder of the brain charac⁃terized by abnormal neuron excitability.However,the underlying molecular mechanism of neuron excitability modulation remains elusive.With the help of bioinformatic methods,we have identified receptor-type tyrosine-pro⁃tein phosphatase-like N(PTPRN)as a critical gene dur⁃ing epileptogenesis.PTPRN recruits NEDD4L ubiquitin E3 ligase to NaV1.2 sodium channels,facilitating NEDD4Lmediated ubiquitination and endocytosis.Knockout of PTPRN endows hippocampal granule cells with augmented depolarization currents and higher intrinsic excitability,which is reflected by increased seizure susceptibility of transgenic mice.On the contrary,reduced neuron excit⁃ability and decreased seizure susceptibility are observed after PTPRN overexpression.Meanwhile,we find that a 133 aa fragment recaptures modulation effect of PTPRN full-length,and this fragment shows therapeutic potential towards epilepsy caused by NaV1.2 gain of function vari⁃ants.In brief,our results demonstrate PTPRN plays a criti⁃cal role in regulating neuron excitability,providing a poten⁃tial therapeutic approach for epilepsy.展开更多
基金National Natural Science Foundation of China(913322028122100381603084).
文摘Temporal lobe epilepsy(TLE) is a common type of epilepsy and is not well controlled by current treatments.The frequent failure to treat TLE may be due to our lack of precise cellular/circuit mechanisms underlying TLE.The early series of our studies have proved the success of low-frequency stimulation treatment for epilepsy,which was mainly depending on the stimulation target,the stimulation frequency and stimulation time(the therapeutic-window phenomenon).Now,by using optogenetics,viral tracing,multiple-channel EEG analysis,imaging,electrophysiology and pharmacology strategies,we are continued to investigate the circuit mechanism of therapeutic deep brain stimulation,and found that entorhinal principal neurons mediate antiepileptic ″ glutamatergic-GABAergic″ neuronal circuit for brain stimulation treatments of epilepsy.Meanwhile,we are currently focusing on the interplay of inhibitory and excitatory network in the key input/output regions of the hippocampus that related to the generation of in TLE.Specially,we found that depolarized GABAergic signaling in subicular microcircuit mediates generalized seizures in TLE and a direct septal cholinergic circuit attenuates TLE through driving hippocampal somatostatin inhibition.These findings may be of therapeutic interest in understanding the pathological neuronal circuitry in TLE and further the development of novel therapeutic approaches or drug targets.
基金National Natural Science Foundation of China(81571269)Science Technology Innovation Fund of Nanjing Medical University (2017NJMUCX008).
文摘OBJECTIVE To study the function of neuronal nitric oxide synthase(nNOS) in the dentate gyrus(DG) in the pathology of epilepsy.METHODS The expression of nNOS in the DG was measured by qPCR and Western blotting in mice 3 and 12 h,1,7,14,and 60 d after treatment with pilocarpine(280 mg·kg-1,ip,one time).We constructed a type of lentiovirus encoding the full length cDNA of nNOS(LV-nNOS-GFP) and injected it and LV-GFP(1 μL) into the DG of the hippocampus 7 d after pilocarpine-induced seizure.The occurrence of epileptic spikes and spontaneous seizure(SRS)were monitored through electroencephalo-graph(EEG) and the protein expression was confirmed by Western blotting.We also constructed a lentioviral vehicle to interfere the expression of nNOS mRNA,which was named as LV-n NOSRNAi-GFP.A volume of 1 μL of LV-nNOS-RNAiGFP or LV-GFP was injected into the DG of the hippocampus 7 d before pilocarpine-induced seizure followed by EEG record and protein detection 2 months later.By EEG,we compared the susceptibility of nNOS knockout and wild-type mice to seizure induction and the development of epilepsy.In addition,we measured the influence of nNOS knockout on the excitability of dentate cells including mEPSC and mIPSC by using patch clamp technique.RESULTS Western blotting and qPCR measurement showed that the mRNA and protein expression of nNOS in the DG was not significantly changed in pilocarpinetreated mice compared with control mice.But the both m RNA and protein expression of nNOS decreased 7,14 and 60 d after treatment with pilocarpine(280 mg·kg-1,ip,one time).With infection of LV-nNOS-GFP in the DG,the decreased level of nNOS was recovered 7 d after seizure induction and the frequency of epileptic spikes and SRS were reversed by nNOS overexpression.We found that nNOS knockout caused a higher susceptive level to seizure induction by pilocarpine.Re-expression of nNOS in the DG of nNOS knockout mice relived the severity of epilepsy.By patch clamp recording,we found that there was no significant difference in the amplitude of mEPSC and mIPSC between nNOS knockout and wild-type mice,but the frequency of mEPSC was increased in nN OS knockout mice.Consistently,knockdown of nNOS by injection of LV-nNOS-RNAi-GFP into the DG caused higher frequency of epileptic spikes and SRS 2 months after pilocarpine-induced seizure.CONCLUSION Neurons expressing nNOS in the DG play an important role in the development of epilepsy.
基金CAMS Innovation Fund for Medical Sciences(2017-I2M-2-004).
文摘OBJECTIVE To examine whether17 AAG and STA9090 have anticonvulsant activity in absence epilepsy.METHODS For the acute seizure study,each group of mice received VPA(dissolved in saline) 100 mg·kg-1,17 AAG(dissolved in 50 μL DMSO) 25 mg·kg-1 or STA9090(dissolved in 20 μL DMSO) 50 mg·kg-1 by oral gavage respectively.The control group received DMSO alone.Thirty minutes after oral gavage,PTZ 80 mg·kg-1 was intraperitoneal injected to induce acute seizures.The number of seizures refers to the total number of epileptic mice after PTZ application.Seizure latency was defined by the time elapsed from PTZ injection to the occurrence of the first seizure.The levels of Hsp90β,GLT-1,GFAP and 20 S proteasome β1 in the cortex and hippocampus were detected by Western blotting.RESULTS The mortality were60% for 17 AAG and 43% for STA9090,and the mortality of valproate group dropped to 20%which decreased by 33.3% compared to model group.Seizure latency of valproate group obviously prolonged compared to model group(P<0.05).But the results demonstrated that 17 AAG and STA9090 had no significant differences in seizure latency.The result of Western blotting has shown that inhibition of Hsp90β significantly reduced expressions of both membrane and cytosolic Hsp90β in the hippocampus and cortex of each group of mice.However,the expressions of GLT-1 and GFAP did not show the significant difference in the cortex and hippocampus.The expression of 20 S proteasome β1 had not been obviously changed in the cortex and hippocampus among the groups.CONCLUSION 17 AAG and STA9090 did not have anticonvulsant activity and did not increase the stability of GLT-1 by disrupting proteasome-dependent GLT-1 degradation in PTZ induced mice of absence epilepsy.
基金National Natural Science Foundation of China(91332202,81630098,81521062,81671282,81703480).
文摘OBJECTIVE To understand the underlying mechanisms of drug resistant temporal lobe epilepsy(TLE).METHODS In vivo and vitro electrophysiology,optogenetics and chemogenetics were used in a classic multi-drug resistant TLE model.RESULTS Subicular pyramidal neuron activity was not inhibited by the anti-epileptic drug phenytoin in drug resistant rats.This phenomenon was specific to the subiculum,but did not involve surrounding temporal lobe regions.Selective inhibition of subicular pyramidal neurons by both optogenetics and chemogenetics reversed drug resistance.In contrast,selective activation of subicular pyramidal neurons directly induced drug resistance in drug responsive rats.Furthermore,long-term low frequency stimulation at the subiculum,which is clinically feasible,inhibited the activity of subicular pyramidal neurons and reversed drug resistance.CONCLUSION Subicular pyramidal neurons might be a key ″ switch″ mediating drug resistance in TLE and represent a new potential target for more precise treatment of drug resistant TLE.
基金The project supportedp by National Natural Science Foundation of China(91332202,81221003)
文摘OBJECTIVE Temporal lobe epilepsy(TLE)is one of the most common types of human epilepsy,and they are often resistant to current treatments.METHODS By using optogenetic,electrophysiological,imaging and pharmacology strategies,we aimed toinvestigate the underlying circuit mechanism of TLE and tried to developthe novel and efficient approach to control epilepsy.RESULTS(1)Using micro PET and multichannel EEG recording,we found an abnormal neural network,characterized by early hypometabolism and after discharge spread,during the epileptogenensis of TLE.(2)Deep brain stimulation,especially low frequency stimulation,targeted the epileptic focus and the areas outside of the focus(critical regions for seizure spread),such as the piriform cortex,cerebellum,entorhinal cortex or subiculum,reduced seizure severity in TLE.Its anti-epileptic effect is time-window dependent and polarity dependent,which shows a promising strategy for treating epileptic seizures.(3)Using an optogenetic strategy,we demonstrated that excitatory projection from entorhinal cortex to hippocampus instructs the brain-stimulation treatments of epilepsy.(4)Our data from both the clinical and experimental studies further demonstrated that a disinhibitory GABAergic neuronmediated microcircuit in the subiculum contributes to secondary generalized seizures in TLE.(5)Finally,based on abnormal synchronization of the electrical activity in epileptic circuit,we developed electroresponsive hydrogel nanoparticles modified with angiopep-2 to facilitate the delivery of the antiepileptic drug phenytoin sodium,which greatly improves the therapeutic index.CONCLUSION Our findings may update the current view of epileptic neuronal networks and suggest possible promising ways for epilepsy treatment.
文摘Time:December 6-10,2019Venue:Baltimore Convention Center,Baltimore MD,USA Website:https://meeting.aesnet.org/American Epilepsy Society(AES)2019 Annual Meeting will take place in Baltimore Convention Center,Baltimore MD,USA on December 6-10,2019.From best practices to breakthrough research,the AES 2019 Annual Meeting offers the most extensive education on everything epilepsy and an unparalleled opportunity to network with the brightest minds in the field.
文摘Time:December 6-10,2019Venue:Baltimore Convention Center,Baltimore MD,USA Website:https://meeting.aesnet.org/American Epilepsy Society(AES)2019 Annual Meeting will take place in Baltimore Convention Center,Baltimore MD,USA on December 6-10,2019.From best practices to breakthrough research,the AES 2019 Annual Meeting offers the most extensive education on everything epilepsy and an unparalleled opportunity to network with the brightest minds in the field.
文摘Time：September 11-15,2016Venue：Prague,Czech RepublicEmail：prague@epilepsycongress.orgWebsite：http：//www.epilepsyprague2016.orgThe 12th European Congress on Epileptology（ECE）will take place in Prague,Czech Republic on September 11-15,2016.The congress is now a landmark in the epilepsy community agenda and the Prague 2016 promises to be innovative and engaging.
文摘The input-output relationship of neuronal networks depends heavily on the intrinsic properties of their neuronal elements.Profound changes in intrinsic properties have been observed in various physiological and pathological processes,such as learning,memory and epilepsy.However,the cellular and molecular mechanisms underlying acquired changes in intrinsic excitability are still not fully understood.Here,we demonstrate that ERG3 channels are critically involved in the regulation of intrinsic excitability in hippocampal CA1 pyramidal neurons and DG granule cells.Knock-down of ERG3 channels significantly increases neuronal intrinsic excitability,which is mainly caused by decreased fast afterhyperpolarization,delayed time to the generation of an action potential and enhanced summation of somatic excitatory post-synaptic potentials.Interestingly,the expression level of ERG3 protein is significantly reduced in human and mouse brain tissues with temporal lobe epilepsy.Moreover,ERG3 channel knock-down in hippocampus significantly enhanced seizure susceptibility,while mice treated with ERG3 channel activator NS1643 were less prone to epileptogenesis.Taken together,our results suggest ERG3 channels play an important role in determining the excitability of hippocampal neurons and dysregulation of these channels may be involved in the generation of epilepsy.ERG3 channels may thus be a novel therapeutic target for the prevention of epilepsy.
文摘Maternal health in pregnancy:messages from the 2014 UK Confidential Enquiry into Maternal Death妊娠期孕妇保健:2014年英国孕妇死亡机密询问信息New NICE guidance on diagnosing cancer in general practice全科医学癌症诊断新NICE指南Can technology help reduce risk of harm in patients with epilepsy?技术是否能够降低癫痫患者伤害风险Support for mothers and their families after life-threatening illness in pregnancy and childbirth:a qualitative study
基金The project supported by National Natural Science Foundation of China(91332202,81630098)
文摘OBJECTIVE Temporal lobe epilepsy(TLE) is one of the most common types of human epilepsy,and they are often resistant to current treatments. METHODS By using optogenetic,electrophysiological,imaging and pharmacology strategies,we aimed toinvestigate the underlying circuit mechanism of TLE and tried to developthe novel and efficient approach to control epilepsy. RESULTS(1) Deep brain stimulation,especially low frequency stimulation,targeted the epileptic focus and the areas outside of the focus(critical regions for seizure spread),such as entorhinal cortex or subiculum,reduced seizure severity in TLE. Its anti-epileptic effect is time-window dependent and polarity dependent,which shows a promising strategy for treating epileptic seizures.(2) Using an optogenetic strategy,we demonstrated that excitatory projection from entorhinal cortex to hippocampus instructs the brain-stimulation treatments of epilepsy.(3) Our data from both the clinical and experimental studies further demonstrated that a disinhibitory GABAergic neuron-mediated microcircuit in the subiculum contributes to secondary generalized seizures in TLE.(4) Finally,based on abnormal synchronization of the electrical activity in epileptic circuit,we developed electro-responsive hydrogel nanoparticles modified with angiopep-2to facilitate the delivery of the antiepileptic drug phenytoin sodium,which greatly improves the therapeutic index. CONCLUSION Our findings may update the current view of epileptic neuronal networks and suggest possible promising ways for epilepsy treatment.
文摘2019年10月,罗巍主任医师团队在《运动疾病》(Movement Disorders)发表了其关于家族性皮质肌阵挛性震颤癫痫(FCMTE)的最新研究成果(https://onlinelibrary.wiley.com/doi/abs/10.1002/mds.27832),文章题目为“Intronie(TTTGA)。insertion in SAMD12 also causes familial cortical myoclonice tremor with epilepsy”自2018年6月罗巍主任医师团队鉴定出位于SAMD12基因4号内含子区的(TTTCA)。五核苷酸重复扩增插入为中国FCMTE患者的主要致病突变后,越来越多的报道证实位于不同基因(日本家系中TNRC6A基因,日本和中国家系RAPGEF2基因,泰国家系YEATS2基因)内含子区的(TTTCA)。五核苷酸重复扩增插人为FCMTE的致病突变。在欧洲FCMTE患者中,也发现位于2号染色体和5号染色体上不同基因内含子区的(TTTCA),五核苷酸重复扩增插人致病。上述研究提示FCMTE的致病突变存在(TTTCA)。序列特异性。
文摘关于收缩压和舒张压的表示方法,经检索相关心血管权威杂志《Circulation》及编辑部讨论,认为先收缩压,后舒张压的表示方法为妥,且首次出现须注明中英文,具体表示方法为,收缩压（SBP）/舒张压（DBP）：120/90 mm Hg。关于Epilepsy的中文翻译应采用＂癫痫＂：根据2013年6月5日国务院公布的《通用规范汉字表》,弃用原全国科技名词审定委员会审定的词＂癫（合成字）＂,采用《通用规范汉字表》中的词＂癫痫＂。
文摘T1-1 PTPRN mediates endocytosis of NaV1.2 sodium chan⁃nels and suppresses epileptogenesis in mice WANG Yifan1,2*,YANG Hui1,2*,LI Na1,2*,MA Weining3,LIU Shiqi1,2,CHEN Hedan1,2,SONG Huifang1,2,MA Xinyue1,2,YI Jingyun1,2,LIAN Jingjing1,2,TU Xinyu1,2,PENG Chao1,2,HUANG Zhuo1,2(1.State Key Laboratory of Natural and Biomimetic Drugs,Department of Molecular and Cellular Pharmacology,School of Pharmaceutial Sciences,Peking University,Beijing 100191,China;2.IDG/McGovern Institute for Brain Research,Peking University,Beijing 100871,China;3.Department of Neurology,Shengjing Hospital Affiliated to China Medical University,Shenyang 110000,China)Abstract:Epilepsy is a disorder of the brain charac⁃terized by abnormal neuron excitability.However,the underlying molecular mechanism of neuron excitability modulation remains elusive.With the help of bioinformatic methods,we have identified receptor-type tyrosine-pro⁃tein phosphatase-like N(PTPRN)as a critical gene dur⁃ing epileptogenesis.PTPRN recruits NEDD4L ubiquitin E3 ligase to NaV1.2 sodium channels,facilitating NEDD4Lmediated ubiquitination and endocytosis.Knockout of PTPRN endows hippocampal granule cells with augmented depolarization currents and higher intrinsic excitability,which is reflected by increased seizure susceptibility of transgenic mice.On the contrary,reduced neuron excit⁃ability and decreased seizure susceptibility are observed after PTPRN overexpression.Meanwhile,we find that a 133 aa fragment recaptures modulation effect of PTPRN full-length,and this fragment shows therapeutic potential towards epilepsy caused by NaV1.2 gain of function vari⁃ants.In brief,our results demonstrate PTPRN plays a criti⁃cal role in regulating neuron excitability,providing a poten⁃tial therapeutic approach for epilepsy.
