Patel Dipan C, Thompson Emily G, Sontheimer Harald
Glial Biology in Health, Disease, and Cancer Center, Fralin Biomedical Research Institute at Virginia Tech-Carilion, Roanoke, VA, United States.
Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL, United States.
Front Cell Dev Biol. 2022 Jul 8;10:961292. doi: 10.3389/fcell.2022.961292. eCollection 2022.
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.
超过100种不同的病毒可感染大脑并引发脑部炎症。在发展中世界，脑部炎症是癫痫的主要病因，且往往对已有的抗癫痫药物耐药。癫痫通常源于兴奋性谷氨酸能神经传递和抑制性γ-氨基丁酸能神经传递之间的失衡。γ-氨基丁酸能抑制作用由细胞内氯离子浓度决定，而细胞内氯离子浓度是通过两种阳离子氯共转运体即NKCC1和KCC2的相反作用建立的。已知脑源性神经营养因子（BDNF）信号传导可调节KCC2的表达。因此，我们推测病毒诱导的癫痫可能源于BDNF信号异常。我们使用泰勒氏鼠脑脊髓炎病毒（TMEV）感染诱导癫痫的小鼠模型来验证这一假设。我们发现，患有癫痫的TMEV感染小鼠海马体中的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的潜伏期和慢性期持续升高。在癫痫急性期，我们发现海马体中KCC2的表达显著降低，而NKCC1的水平未改变。重要的是，在患有癫痫的TMEV感染小鼠的活脑切片中，使用BDNF的清除体抑制BDNF可使海马体中KCC2的水平恢复正常。我们的结果表明，BDNF可直接降低NKCC1和KCC2的相对表达，从而有利于细胞内氯离子的积累，进而通过逆转γ-氨基丁酸介导的抑制作用导致兴奋性过高。尽管我们尝试使用一种小肽抑制通过酪氨酸激酶B-磷脂酶Cγ1（TrkB-PLCγ1）介导的BDNF信号传导，但并未改变TMEV感染后癫痫发作的发展进程，但在该模型中，控制BDNF信号传导的替代策略可能有助于预防癫痫发作和癫痫的发展。
