Experimental Epilepsy Group, Department of Clinical Sciences, Faculty of Medicine, Lund University, Sölvegatan 17, BMC A11, 22362 Lund, Sweden.
Epilepsy Center, Department of Clinical Sciences, Faculty of Medicine, Lund University, Sölvegatan 17, BMC A11, 22362 Lund, Sweden.
Int J Mol Sci. 2022 Oct 29;23(21):13190. doi: 10.3390/ijms232113190.
Glial cell line-derived neurotrophic factor (GDNF) has been shown to counteract seizures when overexpressed or delivered into the brain in various animal models of epileptogenesis or chronic epilepsy. The mechanisms underlying this effect have not been investigated. We here demonstrate for the first time that GDNF enhances GABAergic inhibitory drive onto mouse pyramidal neurons by modulating postsynaptic GABA receptors, particularly in perisomatic inhibitory synapses, by GFRα1 mediated activation of the Ret receptor pathway. Other GDNF receptors, such as NCAM or Syndecan3, are not contributing to this effect. We observed similar alterations by GDNF in human hippocampal slices resected from epilepsy patients. These data indicate that GDNF may exert its seizure-suppressant action by enhancing GABAergic inhibitory transmission in the hippocampal network, thus counteracting the increased excitability of the epileptic brain. This new knowledge can contribute to the development of novel, more precise treatment strategies based on a GDNF gene therapy approach.
胶质细胞源性神经营养因子（GDNF）在各种癫痫发生或慢性癫痫的动物模型中过度表达或递送至大脑时，已被证明可对抗癫痫发作。但其作用机制尚未被研究。我们首次证明，GDNF 通过 GFRα1 介导的 Ret 受体途径的激活，调节突触后 GABA 受体，特别是在体周抑制性突触上，增强 GABA 能抑制性驱动至小鼠锥体神经元。其他 GDNF 受体，如 NCAM 或 Syndecan3，对这种作用没有贡献。我们在从癫痫患者切除的人类海马切片中观察到 GDNF 产生了类似的改变。这些数据表明，GDNF 可能通过增强海马网络中的 GABA 能抑制性传递来发挥其抑制癫痫发作的作用，从而抵消癫痫大脑的过度兴奋。这一新知识可以为基于 GDNF 基因治疗方法的新型、更精确的治疗策略的发展做出贡献。
