Disruption of the sodium-dependent citrate transporter SLC13A5 in mice causes alterations in brain citrate levels and neuronal network excitability in the hippocampus
Disruption of the sodium-dependent citrate transporter SLC13A5 in mice causes alterations in brain citrate levels and neuronal network excitability in the hippocampus
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DOI：
10.1016/j.nbd.2020.105018
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发表时间：
2020-09-01
影响因子：
6.1
通讯作者：
Loscher, Wolfgang
中科院分区：
文献类型：
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作者：
Henke, Christine;Tollner, Kathrin;Loscher, Wolfgang
除了肝脏等组织外，质膜钠依赖性柠檬酸盐转运蛋白NaCT（SLC 13 A5）在脑神经元中高度表达，但其功能尚不清楚。人类SLC 13 A5基因的功能缺失突变与严重新生儿脑病和耐药性癫痫发作相关。这些神经学改变的分子机制尚不清楚。我们对Slc 13 a5缺失小鼠模型进行了详细的检查，包括视频EEG监测，行为测试，以及脑和脑脊液的电生理，蛋白质组学和代谢组学分析。实验表明，增加的倾向癫痫发作，proepileptogenic神经元兴奋性变化的海马，并显着的柠檬酸盐改变的CSF和脑组织的Slc 13 a5缺陷型小鼠，这可能是神经系统异常的基础。这些数据表明，SLC 13 A5参与脑柠檬酸盐调节，并表明这种调节的异常可诱导癫痫发作。本研究是第一个（i）建立Slc 13 a5基因敲除小鼠模型作为研究NaCT神经功能的有用工具，并表征这种柠檬酸盐转运蛋白功能缺陷引起癫痫和损害神经功能的分子机制;（ii）评估先前在理论基础上提出的解释SLC 13 A5突变的神经学表型的所有假设;和（iii）表明脑柠檬酸盐水平的改变导致神经元网络兴奋性和癫痫倾向增加。
In addition to tissues such as liver, the plasma membrane sodium-dependent citrate transporter, NaCT (SLC13A5), is highly expressed in brain neurons, but its function is not understood. Loss-of-function mutations in the human SLC13A5 gene have been associated with severe neonatal encephalopathy and pharmacoresistant seizures. The molecular mechanisms of these neurological alterations are not clear. We performed a detailed examination of a Slc13a5 deletion mouse model including video-EEG monitoring, behavioral tests, and electrophysiologic, proteomic, and metabolomic analyses of brain and cerebrospinal fluid. The experiments revealed an increased propensity for epileptic seizures, proepileptogenic neuronal excitability changes in the hippocampus, and significant citrate alterations in the CSF and brain tissue of Slc13a5 deficient mice, which may underlie the neurological abnormalities. These data demonstrate that SLC13A5 is involved in brain citrate regulation and suggest that abnormalities in this regulation can induce seizures. The present study is the first to (i) establish the Slc13a5-knockout mouse model as a helpful tool to study the neuronal functions of NaCT and characterize the molecular mechanisms by which functional deficiency of this citrate transporter causes epilepsy and impairs neuronal function; (ii) evaluate all hypotheses that have previously been suggested on theoretical grounds to explain the neurological phenotype of SLC13A5 mutations; and (iii) indicate that alterations in brain citrate levels result in neuronal network excitability and increased seizure propensity.