Brain-Derived Neurotrophic Factor Inhibits the Function of Cation-Chloride Cotransporter in a Mouse Model of Viral Infection-Induced Epilepsy.
Brain-Derived Neurotrophic Factor Inhibits the Function of Cation-Chloride Cotransporter in a Mouse Model of Viral Infection-Induced Epilepsy.
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DOI：
10.3389/fcell.2022.961292
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发表时间：
2022
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
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超过100种不同的病毒可以感染大脑并导致脑部炎症。在发展中国家，脑部炎症是癫痫的主要原因，而且通常对已有的抗癫痫药物无效。癫痫通常是由于兴奋性谷氨酸能和抑制性GABA能神经传递失衡所致。GABA能抑制是由细胞内的氯−浓度决定的，该浓度是通过两个阳离子氯化物共转运体NKCC1和KCC2的相反作用而建立的。脑源性神经营养因子(BDNF)信号转导调节KCC2的表达。因此，我们假设病毒诱导的癫痫可能是由BDNF信号的异常引起的。我们使用泰勒氏小鼠脑脊髓炎病毒(TMEV)感染诱发癫痫的小鼠模型验证了这一假设。我们发现，TMEV感染癫痫小鼠的海马区BDNF水平在急性癫痫发作开始时升高，并在急性癫痫发作高峰期以及癫痫潜伏期和慢性期继续增加。在癫痫急性期，我们发现KCC2在海马区的表达显著降低，而NKCC1的表达水平没有变化。重要的是，使用TMEV感染癫痫小鼠活脑片中BDNF的清除体来抑制BDNF，可以使海马区KCC2的水平正常化。我们的结果表明，BDNF可以直接降低NKCC1和KCC2的相对表达，从而有利于细胞内氯的积累，从而通过逆转GABA介导的抑制而导致过度兴奋。尽管我们试图用一种小肽抑制酪氨酸激酶B-磷脂酶Cγ1(TrkB-PLCγ1)介导的脑源性神经营养因子信号转导，但在该模型中，控制脑源性神经营养因子信号转导的替代策略可能有助于预防癫痫的发生和发展。
Well over 100 different viruses can infect the brain and cause brain inflammation. In the developing world, brain inflammation is a leading cause for epilepsy and often refractory to established anti-seizure drugs. Epilepsy generally results from an imbalance in excitatory glutamatergic and inhibitory GABAergic neurotransmission. GABAergic inhibition is determined by the intracellular Cl− concentration which is established through the opposing action of two cation chloride cotransporters namely NKCC1 and KCC2. Brain-derived neurotrophic factor (BDNF) signaling is known to regulate expression of KCC2. Hence we hypothesized that viral induced epilepsy may result from aberrant BDNF signaling. We tested this hypothesis using a mouse model of Theiler’s murine encephalomyelitis virus (TMEV) infection-induced epilepsy. We found that BDNF levels in the hippocampus from TMEV-infected mice with seizures was increased at the onset of acute seizures and continued to increase during the peak of acute seizure as well as in latent and chronic phases of epilepsy. During the acute phase of epilepsy, we found significant reduction in the expression of KCC2 in hippocampus, whereas the level of NKCC1 was unaltered. Importantly, inhibiting BDNF using scavenging bodies of BDNF in live brain slices from TMEV-infected mice with seizures normalized the level of KCC2 in hippocampus. Our results suggest that BDNF can directly decrease the relative expression of NKCC1 and KCC2 such as to favor accumulation of chloride intracellularly which in turn causes hyperexcitability by reversing GABA-mediated inhibition. Although our attempt to inhibit the BDNF signaling mediated through tyrosine kinase B–phospholipase Cγ1 (TrkB-PLCγ1) using a small peptide did not change the course of seizure development following TMEV infection, alternative strategies for controlling the BDNF signaling could be useful in preventing seizure generation and development of epilepsy in this model.
影响因子：
5.6
作者：
Juda MB;Brooks AK;Towers AE;Freund GG;McCusker RH;Steelman AJ
通讯作者：
Steelman AJ