Department of Neurology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.
Department of Pediatrics, Yiwu Maternal and Child Health Care Hospital, Yiwu, China.
Mol Neurobiol. 2022 Nov;59(11):6918-6933. doi: 10.1007/s12035-022-02993-2. Epub 2022 Sep 2.
Epilepsy is a chronic brain disease that makes serious cognitive and motor retardation. Ion channels affect the occurrence of epilepsy in various ways, but the mechanisms have not yet been fully elucidated. Transient receptor potential melastain2 (TRPM2) ion channel is a non-selective cationic channel that can permeate Ca and critical for epilepsy. Here, TRPM2 gene knockout mice were used to generate a chronic kindling epilepsy model by PTZ administration in mice. We found that TRPM2 knockout mice were more susceptible to epilepsy than WT mice. Furthermore, the neuronal excitability in the hippocampal CA1 region of TRPM2 knockout mice was significantly increased. Compared with WT group, there were no significant differences in the input resistance and after hyperpolarization of CA1 neurons in TRPM2 knockout mice. Firing adaptation rate of hippocampal CA1 pyramidal neurons of TRPM2 knockout mice was lower than that of WT mice. We also found that activation of Kv7 channel by retigabine reduced the firing frequency of action potential in the hippocampal pyramidal neurons of TRPM2 knockout mice. However, inhibiting Kv7 channel increased the firing frequency of action potential in hippocampal pyramidal neurons of WT mice. The data suggest that activation of Kv7 channel can effectively reduce epileptic seizures in TRPM2 knockout mice. We conclude that genetic knockout of TRPM2 in hippocampal CA1 pyramidal neurons may increase neuronal excitability by inhibiting Kv7 channel, affecting the susceptibility to epilepsy. These findings may provide a potential therapeutic target for epilepsy.
癫痫是一种慢性脑部疾病，会导致严重的认知和运动障碍。离子通道以各种方式影响癫痫的发生，但机制尚未完全阐明。瞬时受体电位 melastain2（TRPM2）离子通道是一种非选择性阳离子通道，可渗透 Ca，并对癫痫至关重要。在这里，使用 TRPM2 基因敲除小鼠通过 PTZ 给药在小鼠中产生慢性点燃癫痫模型。我们发现 TRPM2 基因敲除小鼠比 WT 小鼠更容易患癫痫。此外，TRPM2 基因敲除小鼠海马 CA1 区的神经元兴奋性显着增加。与 WT 组相比，TRPM2 基因敲除小鼠 CA1 神经元的输入电阻和超极化后没有显着差异。TRPM2 基因敲除小鼠海马 CA1 锥体神经元的放电适应率低于 WT 小鼠。我们还发现，通过 retigabine 激活 Kv7 通道可降低 TRPM2 基因敲除小鼠海马锥体神经元中动作电位的放电频率。然而，抑制 Kv7 通道会增加 WT 小鼠海马锥体神经元中动作电位的放电频率。数据表明，激活 Kv7 通道可有效减少 TRPM2 基因敲除小鼠的癫痫发作。我们得出结论，海马 CA1 锥体神经元中 TRPM2 的基因敲除可能通过抑制 Kv7 通道增加神经元兴奋性，从而影响癫痫易感性。这些发现可能为癫痫提供潜在的治疗靶点。
