The Notch pathway is well known as a master regulator of neural stem cells, but accumulating evidence suggest both novel and sophisticated roles for Notch signaling in adult brain. In the postnatal hippocampus, the regulatory function of Notch signaling on synaptic plasticity has been studied extensively. Mice with germline deletion of Notch1 or presenilins exhibited impaired long-term potentiation (LTP) and working memory, which could be understood as a consequence of disruptions in Notch-dependent neurite development and neuronal migration. Compared with long-term synaptic plasticity, recent studies have shown that Notch pathway is induced instantly by neuronal activity, suggesting a correlate of stimulus-dependent Notch activity and synaptic transmission. However, the role of those non-canonical functions of Notch signaling in neurological disorders has not been characterized so far. More recently, we have reported that Notch signaling activation led to an increase in epileptiform discharges in a mouse model of acute seizures. Temporal lobe epilepsy (TLE) is among the most frequent types of drug-resistant epilepsy, and the reorganization of neural circuits underlying the generation of recurrent seizures has been demonstrated, including impaired long-term potentiation of synaptic networks and disordered short-term synaptic responses. Here, focusing on the primary and new-emerging functions of Notch signaling, we review the complicated roles of Notch in the development of TLE and speculate some potential neuropathogenic mechanisms.
{"title":"Complex Roles of Notch Signaling in the Development of Temporal Lobe Epilepsy: Evidence and Speculation","authors":"Longze Sha, Qi Xu","doi":"10.14800/MCE.22","DOIUrl":"https://doi.org/10.14800/MCE.22","url":null,"abstract":"The Notch pathway is well known as a master regulator of neural stem cells, but accumulating evidence suggest both novel and sophisticated roles for Notch signaling in adult brain. In the postnatal hippocampus, the regulatory function of Notch signaling on synaptic plasticity has been studied extensively. Mice with germline deletion of Notch1 or presenilins exhibited impaired long-term potentiation (LTP) and working memory, which could be understood as a consequence of disruptions in Notch-dependent neurite development and neuronal migration. Compared with long-term synaptic plasticity, recent studies have shown that Notch pathway is induced instantly by neuronal activity, suggesting a correlate of stimulus-dependent Notch activity and synaptic transmission. However, the role of those non-canonical functions of Notch signaling in neurological disorders has not been characterized so far. More recently, we have reported that Notch signaling activation led to an increase in epileptiform discharges in a mouse model of acute seizures. Temporal lobe epilepsy (TLE) is among the most frequent types of drug-resistant epilepsy, and the reorganization of neural circuits underlying the generation of recurrent seizures has been demonstrated, including impaired long-term potentiation of synaptic networks and disordered short-term synaptic responses. Here, focusing on the primary and new-emerging functions of Notch signaling, we review the complicated roles of Notch in the development of TLE and speculate some potential neuropathogenic mechanisms.","PeriodicalId":18603,"journal":{"name":"Molecular & Cellular Epilepsy","volume":"141 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2014-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85369301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Clarification of refractory epilepsy mechanisms is of great significance for its precise diagnosis and adequate therapeutic approach. This review presents current hypotheses of refractory epilepsy formation: 1. Hypothesis of genetic factors; 2. Hypothesis of multi-drug transporters; 3. Target hypothesis; 4. Hypothesis of mechanisms related to antiepileptic drugs – development of tolerance and ineffective mechanisms of action 5. Hypothesis of epilepsy related factors – seizure etiology, epilepsy progression, structural brain changes or neural net alterations. The latter hypothesis is closely related to the hypothesis of intrinsic severity as a determinant of antiepileptic drug resistance. A combination of mechanisms is also a possible explanation of refractoriness. Each of these hypotheses characterizes refractory epilepsy to a different extent without attaining an explicit and complex explanation of epileptogenesis.
{"title":"Basic cellular and molecular mechanisms of refractory epilepsy: a review of current hypotheses","authors":"E. Viteva","doi":"10.14800/MCE.17","DOIUrl":"https://doi.org/10.14800/MCE.17","url":null,"abstract":"Clarification of refractory epilepsy mechanisms is of great significance for its precise diagnosis and adequate therapeutic approach. This review presents current hypotheses of refractory epilepsy formation: 1. Hypothesis of genetic factors; 2. Hypothesis of multi-drug transporters; 3. Target hypothesis; 4. Hypothesis of mechanisms related to antiepileptic drugs – development of tolerance and ineffective mechanisms of action 5. Hypothesis of epilepsy related factors – seizure etiology, epilepsy progression, structural brain changes or neural net alterations. The latter hypothesis is closely related to the hypothesis of intrinsic severity as a determinant of antiepileptic drug resistance. A combination of mechanisms is also a possible explanation of refractoriness. Each of these hypotheses characterizes refractory epilepsy to a different extent without attaining an explicit and complex explanation of epileptogenesis.","PeriodicalId":18603,"journal":{"name":"Molecular & Cellular Epilepsy","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2014-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81221601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Idiopathic Absence Epilepsies (IAE) are complex syndromes with a strong genetic component. Childhood absence Epilepsy (CAE) is a common form of IAE, affecting children between the age of 3 and 8 years old and that has been associated with mutations in the GABA A receptor. Particularly, a R43Q mutation on the g2 subunit, which impairs GABA A receptor function, has been clearly linked to CAE in animal models and patients. The same mutation has also been linked to febrile seizures, another epileptic syndrome, characterized by a later onset than CAE. GABA is the major inhibitory neurotransmitter in the brain, and dysregulation of GABA synaptic transmission can have drastic effects on neuronal excitability. It is therefore not surprising that mutations impairing the activity of GABA A receptors are involved in epileptic pathologies. This research highlight describes our latest study, dissecting the effect of the R43Q mutation on the receptor’s function.
{"title":"The γ2(R43Q) mutation linked to epilepsy affects GABAA receptor internalization","authors":"S. Chaumont, M. Garret","doi":"10.14800/MCE.24","DOIUrl":"https://doi.org/10.14800/MCE.24","url":null,"abstract":"Idiopathic Absence Epilepsies (IAE) are complex syndromes with a strong genetic component. Childhood absence Epilepsy (CAE) is a common form of IAE, affecting children between the age of 3 and 8 years old and that has been associated with mutations in the GABA A receptor. Particularly, a R43Q mutation on the g2 subunit, which impairs GABA A receptor function, has been clearly linked to CAE in animal models and patients. The same mutation has also been linked to febrile seizures, another epileptic syndrome, characterized by a later onset than CAE. GABA is the major inhibitory neurotransmitter in the brain, and dysregulation of GABA synaptic transmission can have drastic effects on neuronal excitability. It is therefore not surprising that mutations impairing the activity of GABA A receptors are involved in epileptic pathologies. This research highlight describes our latest study, dissecting the effect of the R43Q mutation on the receptor’s function.","PeriodicalId":18603,"journal":{"name":"Molecular & Cellular Epilepsy","volume":"123 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2014-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91497434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Despite there exist obvious metabolic changes within brain after subthalamic nucleus stimulation for refractory epilepsy, our understanding about the neuroanatomical and neurochemical mechanisms of subthalamic nucleus stimulation is still limited. Melanocortin receptor subtype 4 (MC4R) has been shown to mediate melanocortin effects on cerebral glucose metabolism, and, recently, to modulate astrocyte functions. This review described that subthalamic nucleus stimulation involved in the changes in regional cerebral glucose metabolism, and MC4R signaling in the brain. We discussed the possible therapeutic mechanism of subthalamic nucleus stimulation for refractory epilepsy. It is highlighted that improvement of epileptic signs associated with subthalamic nucleus stimulation might involve in melanocortin-4 receptor signaling on neurons and astrocytes, not only in the target, but also in surrounding and remote connecting regions.
{"title":"Therapeutic mechanism of subthalamic nucleus stimulation for refractory epilepsy involved in melanocortin-4 receptor signaling","authors":"Hongbing Xiang","doi":"10.14800/MCE.18","DOIUrl":"https://doi.org/10.14800/MCE.18","url":null,"abstract":"Despite there exist obvious metabolic changes within brain after subthalamic nucleus stimulation for refractory epilepsy, our understanding about the neuroanatomical and neurochemical mechanisms of subthalamic nucleus stimulation is still limited. Melanocortin receptor subtype 4 (MC4R) has been shown to mediate melanocortin effects on cerebral glucose metabolism, and, recently, to modulate astrocyte functions. This review described that subthalamic nucleus stimulation involved in the changes in regional cerebral glucose metabolism, and MC4R signaling in the brain. We discussed the possible therapeutic mechanism of subthalamic nucleus stimulation for refractory epilepsy. It is highlighted that improvement of epileptic signs associated with subthalamic nucleus stimulation might involve in melanocortin-4 receptor signaling on neurons and astrocytes, not only in the target, but also in surrounding and remote connecting regions.","PeriodicalId":18603,"journal":{"name":"Molecular & Cellular Epilepsy","volume":"55 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2014-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85251564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
800x600 Neonatal seizures occur in five of 1000 live births in North America and affect the future development of the child. Preterm neonates are more susceptible to seizures due to brain immaturity with the incidence of 11 of 1000 live births, much higher than neonatal seizures. Few medicines studied and approved to treat this subset of patients, management difficult. The only medicines approved by the FDA are phenytoin and Phenobarbital in the neonatal period. Failure of these agents due to lack of efficacy and undesirable side-effects led us to investigate the role of Intravenous Levetiracetam in preterm neonates, the most challenging group of patients in the pediatric population. In this research highlight, we will discuss the findings of our recent in preterm neonates. Normal 0 false false false EN-US ZH-CN X-NONE MicrosoftInternetExplorer4 st1:*{behavior:url(#ieooui) } /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin:0cm; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:"Times New Roman","serif";}
{"title":"Levetiracetam – An Alternative Option in Preterm Neonates for Acute Seizure Management","authors":"Batool F. Kirmani","doi":"10.14800/MCE.19","DOIUrl":"https://doi.org/10.14800/MCE.19","url":null,"abstract":"800x600 Neonatal seizures occur in five of 1000 live births in North America and affect the future development of the child. Preterm neonates are more susceptible to seizures due to brain immaturity with the incidence of 11 of 1000 live births, much higher than neonatal seizures. Few medicines studied and approved to treat this subset of patients, management difficult. The only medicines approved by the FDA are phenytoin and Phenobarbital in the neonatal period. Failure of these agents due to lack of efficacy and undesirable side-effects led us to investigate the role of Intravenous Levetiracetam in preterm neonates, the most challenging group of patients in the pediatric population. In this research highlight, we will discuss the findings of our recent in preterm neonates. Normal 0 false false false EN-US ZH-CN X-NONE MicrosoftInternetExplorer4 \u0000st1:*{behavior:url(#ieooui) } \u0000 /* Style Definitions */ \u0000 table.MsoNormalTable \u0000 {mso-style-name:\"Table Normal\"; \u0000 mso-tstyle-rowband-size:0; \u0000 mso-tstyle-colband-size:0; \u0000 mso-style-noshow:yes; \u0000 mso-style-priority:99; \u0000 mso-style-parent:\"\"; \u0000 mso-padding-alt:0cm 5.4pt 0cm 5.4pt; \u0000 mso-para-margin:0cm; \u0000 mso-para-margin-bottom:.0001pt; \u0000 mso-pagination:widow-orphan; \u0000 font-size:10.0pt; \u0000 font-family:\"Times New Roman\",\"serif\";}","PeriodicalId":18603,"journal":{"name":"Molecular & Cellular Epilepsy","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2014-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90647290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dawn Gano, Sharon A Orbach, Sonia L Bonifacio, Hannah C Glass
Neonatal seizures are associated with morbidity and mortality. Hypoxic-ischemic encephalopathy (HIE) is the most common cause of seizures in newborns. Neonatal animal models suggest that therapeutic hypothermia can reduce seizures and epileptiform activity in the setting of hypoxia-ischemia, however data from human studies have conflicting results. In this research highlight, we will discuss the findings of our recent study that demonstrated a decreased seizure burden in term newborns with moderate HIE treated with hypothermia.
{"title":"Neonatal seizures and therapeutic hypothermia for hypoxic-ischemic encephalopathy.","authors":"Dawn Gano, Sharon A Orbach, Sonia L Bonifacio, Hannah C Glass","doi":"10.14800/mce.88","DOIUrl":"10.14800/mce.88","url":null,"abstract":"<p><p>Neonatal seizures are associated with morbidity and mortality. Hypoxic-ischemic encephalopathy (HIE) is the most common cause of seizures in newborns. Neonatal animal models suggest that therapeutic hypothermia can reduce seizures and epileptiform activity in the setting of hypoxia-ischemia, however data from human studies have conflicting results. In this research highlight, we will discuss the findings of our recent study that demonstrated a decreased seizure burden in term newborns with moderate HIE treated with hypothermia.</p>","PeriodicalId":18603,"journal":{"name":"Molecular & Cellular Epilepsy","volume":"1 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4456026/pdf/nihms689547.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33243694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：