Local brain environment changes associated with epileptogenesis
Local brain environment changes associated with epileptogenesis
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DOI：
10.1093/brain/awac355
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发表时间：
2022-11-25
期刊：
影响因子：
14.5
通讯作者：
Matsui，Ko
中科院分区：
文献类型：
--
作者：
Ikoma，Yoko;Sasaki，Daichi;Matsui，Ko
神经元系统的可塑性变化传统上被认为主要由突触传递的长时程增强/抑制机制控制。然而，环境离子、递质和代谢物浓度的一个相当简单的变化可能在学习和记忆的生理过程中产生可塑性方面发挥关键作用。局部脑内环境和代谢的改变也可能是导致癫痫发病的原因和后果。控制局部脑环境是星形胶质细胞的主要功能。整个大脑的代谢状态与外侧下丘脑的活动密切相关。在这项研究中，可塑性变化的星形胶质细胞的反应，在外侧下丘脑检查癫痫作为一种极端形式的可塑性。在自由活动的转基因雄性小鼠中，通过体内纤维光度法对星形胶质细胞中表达的钙或pH荧光传感器进行了长达一周的检查。以秒为时间尺度的光学波动很难评估，因为这些信号受到局部脑血容量变化和pH值变化的严重影响。使用一种新设计的光学信号的分析方法，在星形胶质细胞中的Ca 2+和pH值的变化和局部脑血容量的变化与肾上腺素刺激的癫痫发作提取。在神经元过度活跃引发的星形胶质细胞短暂的碱性转变后，出现了一个突出的酸性转变，以响应与点燃发展的癫痫发作加剧。由于观察到局部脑血容量响应于增强的癫痫发作而短暂增加，因此酸性转变是意外的，这应导致酸性CO2的有效排出。酸性转变可能是谷氨酸转运蛋白活性的结果和/或由于星形胶质细胞代谢负荷增加导致CO2和乳酸产生增加。这种酸性转变可能触发星形胶质细胞释放额外的胶质递质，导致癫痫加重。由于所有的细胞酶反应都受到Ca2+和pH的影响，这些参数的变化也可能对神经元回路活动产生影响。因此，控制星形胶质细胞pH和/或Ca2+可能是治疗癫痫或预防与癫痫发生相关的不期望的可塑性的新的治疗靶点。
Plastic change of the neuronal system has traditionally been assumed to be governed primarily by the long-term potentiation/depression mechanisms of synaptic transmission. However, a rather simple shift in the ambient ion, transmitter and metabolite concentrations could have a pivotal role in generating plasticity upon the physiological process of learning and memory. Local brain environment and metabolic changes could also be the cause and consequences of the pathogenesis leading to epilepsy. Governing of the local brain environment is the primal function of astrocytes. The metabolic state of the entire brain is strongly linked to the activity of the lateral hypothalamus. In this study, plastic change of astrocyte reactions in the lateral hypothalamus was examined using epileptogenesis as an extreme form of plasticity. Fluorescent sensors for calcium or pH expressed in astrocytes were examined for up to one week byin vivofibre photometry in freely moving transgenic male mice. Optical fluctuations on a timescale of seconds is difficult to assess because these signals are heavily influenced by local brain blood volume changes and pH changes. Using a newly devised method for the analysis of the optical signals, changes in Ca2+and pH in astrocytes and changes in local brain blood volume associated with hippocampal-stimulated epileptic seizures were extracted. Following a transient alkaline shift in the astrocyte triggered by neuronal hyperactivity, a prominent acidic shift appeared in response to intensified seizure which developed with kindling. The acidic shift was unexpected as transient increase in local brain blood volume was observed in response to intensified seizures, which should lead to efficient extrusion of the acidic CO2. The acidic shift could be a result of glutamate transporter activity and/or due to the increased metabolic load of astrocytes leading to increased CO2and lactate production. This acidic shift may trigger additional gliotransmitter release from astrocytes leading to the exacerbation of epilepsy. As all cellular enzymic reactions are influenced by Ca2+and pH, changes in these parameters could also have an impact on the neuronal circuit activity. Thus, controlling the astrocyte pH and/or Ca2+could be a new therapeutic target for treatment of epilepsy or prevention of undesired plasticity associated with epileptogenesis.