{"title":"癫痫状态引发的 GABAA 受体介导的抑制变化及其在癫痫发生和焦虑增加中的作用。","authors":"","doi":"10.1016/j.nbd.2024.106633","DOIUrl":null,"url":null,"abstract":"<div><p>The triggers of status epilepticus (SE) in non-epileptic patients can vary widely, from idiopathic causes to exposure to chemoconvulsants. Regardless of its etiology, prolonged SE can cause significant brain damage, commonly resulting in the development of epilepsy, which is often accompanied by increased anxiety. GABA<sub>A</sub> receptor (GABA<sub>A</sub>R)-mediated inhibition has a central role among the mechanisms underlying brain damage and the ensuing epilepsy and anxiety. During SE, calcium influx primarily via ionotropic glutamate receptors activates signaling cascades which trigger a rapid internalization of synaptic GABA<sub>A</sub>Rs; this weakens inhibition, exacerbating seizures and excitotoxicity. GABAergic interneurons are more susceptible to excitotoxic death than principal neurons. During the latent period of epileptogenesis, the aberrant reorganization in synaptic interactions that follow interneuronal loss in injured brain regions, leads to the formation of hyperexcitable, seizurogenic neuronal circuits, along with disturbances in brain oscillatory rhythms. Reduction in the spontaneous, rhythmic “bursts” of IPSCs in basolateral amygdala neurons is likely to play a central role in anxiogenesis. Protecting interneurons during SE is key to preventing both epilepsy and anxiety. Antiglutamatergic treatments, including antagonism of calcium-permeable AMPA receptors, can be expected to control seizures and reduce excitotoxicity not only by directly suppressing hyperexcitation, but also by counteracting the internalization of synaptic GABA<sub>A</sub>Rs. Benzodiazepines, as delayed treatment of SE, have low efficacy due to the reduction and dispersion of their targets (the synaptic GABA<sub>A</sub>Rs), but also because themselves contribute to further reduction of available GABA<sub>A</sub>Rs at the synapse; furthermore, benzodiazepines may be completely ineffective in the immature brain.</p></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1000,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S096999612400233X/pdfft?md5=c552af560df42a7e28bede3ce7f9d51e&pid=1-s2.0-S096999612400233X-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Alterations in GABAA receptor-mediated inhibition triggered by status epilepticus and their role in epileptogenesis and increased anxiety\",\"authors\":\"\",\"doi\":\"10.1016/j.nbd.2024.106633\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>The triggers of status epilepticus (SE) in non-epileptic patients can vary widely, from idiopathic causes to exposure to chemoconvulsants. Regardless of its etiology, prolonged SE can cause significant brain damage, commonly resulting in the development of epilepsy, which is often accompanied by increased anxiety. GABA<sub>A</sub> receptor (GABA<sub>A</sub>R)-mediated inhibition has a central role among the mechanisms underlying brain damage and the ensuing epilepsy and anxiety. During SE, calcium influx primarily via ionotropic glutamate receptors activates signaling cascades which trigger a rapid internalization of synaptic GABA<sub>A</sub>Rs; this weakens inhibition, exacerbating seizures and excitotoxicity. GABAergic interneurons are more susceptible to excitotoxic death than principal neurons. During the latent period of epileptogenesis, the aberrant reorganization in synaptic interactions that follow interneuronal loss in injured brain regions, leads to the formation of hyperexcitable, seizurogenic neuronal circuits, along with disturbances in brain oscillatory rhythms. Reduction in the spontaneous, rhythmic “bursts” of IPSCs in basolateral amygdala neurons is likely to play a central role in anxiogenesis. Protecting interneurons during SE is key to preventing both epilepsy and anxiety. Antiglutamatergic treatments, including antagonism of calcium-permeable AMPA receptors, can be expected to control seizures and reduce excitotoxicity not only by directly suppressing hyperexcitation, but also by counteracting the internalization of synaptic GABA<sub>A</sub>Rs. Benzodiazepines, as delayed treatment of SE, have low efficacy due to the reduction and dispersion of their targets (the synaptic GABA<sub>A</sub>Rs), but also because themselves contribute to further reduction of available GABA<sub>A</sub>Rs at the synapse; furthermore, benzodiazepines may be completely ineffective in the immature brain.</p></div>\",\"PeriodicalId\":19097,\"journal\":{\"name\":\"Neurobiology of Disease\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.1000,\"publicationDate\":\"2024-08-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S096999612400233X/pdfft?md5=c552af560df42a7e28bede3ce7f9d51e&pid=1-s2.0-S096999612400233X-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Neurobiology of Disease\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S096999612400233X\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neurobiology of Disease","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S096999612400233X","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
摘要
非癫痫患者出现癫痫状态(SE)的诱因千差万别,从特发性原因到接触化学惊厥剂。无论其病因如何,长时间的癫痫状态都会造成严重的脑损伤,通常会导致癫痫的发生,并常常伴有焦虑加重。GABAA 受体(GABAAR)介导的抑制作用在脑损伤及随之而来的癫痫和焦虑的基本机制中起着核心作用。在 SE 期间,钙流入主要通过离子型谷氨酸受体激活信号级联,从而引发突触 GABAARs 快速内化;这会削弱抑制作用,加剧癫痫发作和兴奋毒性。GABA 能中间神经元比主神经元更容易受到兴奋性毒性的影响而死亡。在癫痫发生的潜伏期,受伤脑区的神经元间丧失后,突触相互作用会发生异常重组,从而形成过度兴奋的癫痫源神经元回路,同时扰乱大脑振荡节奏。杏仁核基底外侧神经元中自发的、有节奏的 "突发 "IPSCs的减少很可能在焦虑发生过程中起着核心作用。在 SE 期间保护中间神经元是预防癫痫和焦虑的关键。抗谷氨酸能治疗(包括拮抗钙离子渗透性 AMPA 受体)不仅能直接抑制过度兴奋,还能抵消突触 GABAARs 的内化,从而有望控制癫痫发作并减少兴奋毒性。苯二氮卓类药物作为 SE 的延迟治疗药物,由于其靶点(突触 GABAARs)的减少和分散而疗效不佳,而且其本身也会导致突触处可用 GABAARs 的进一步减少;此外,苯二氮卓类药物在未成熟的大脑中可能完全无效。
Alterations in GABAA receptor-mediated inhibition triggered by status epilepticus and their role in epileptogenesis and increased anxiety
The triggers of status epilepticus (SE) in non-epileptic patients can vary widely, from idiopathic causes to exposure to chemoconvulsants. Regardless of its etiology, prolonged SE can cause significant brain damage, commonly resulting in the development of epilepsy, which is often accompanied by increased anxiety. GABAA receptor (GABAAR)-mediated inhibition has a central role among the mechanisms underlying brain damage and the ensuing epilepsy and anxiety. During SE, calcium influx primarily via ionotropic glutamate receptors activates signaling cascades which trigger a rapid internalization of synaptic GABAARs; this weakens inhibition, exacerbating seizures and excitotoxicity. GABAergic interneurons are more susceptible to excitotoxic death than principal neurons. During the latent period of epileptogenesis, the aberrant reorganization in synaptic interactions that follow interneuronal loss in injured brain regions, leads to the formation of hyperexcitable, seizurogenic neuronal circuits, along with disturbances in brain oscillatory rhythms. Reduction in the spontaneous, rhythmic “bursts” of IPSCs in basolateral amygdala neurons is likely to play a central role in anxiogenesis. Protecting interneurons during SE is key to preventing both epilepsy and anxiety. Antiglutamatergic treatments, including antagonism of calcium-permeable AMPA receptors, can be expected to control seizures and reduce excitotoxicity not only by directly suppressing hyperexcitation, but also by counteracting the internalization of synaptic GABAARs. Benzodiazepines, as delayed treatment of SE, have low efficacy due to the reduction and dispersion of their targets (the synaptic GABAARs), but also because themselves contribute to further reduction of available GABAARs at the synapse; furthermore, benzodiazepines may be completely ineffective in the immature brain.
期刊介绍:
Neurobiology of Disease is a major international journal at the interface between basic and clinical neuroscience. The journal provides a forum for the publication of top quality research papers on: molecular and cellular definitions of disease mechanisms, the neural systems and underpinning behavioral disorders, the genetics of inherited neurological and psychiatric diseases, nervous system aging, and findings relevant to the development of new therapies.