星形胶质细胞Lrp4在耐药性癫痫发病中的作用及其“自身稳态”突触可塑性调控机制

So far, the treatment for drug-resistant/refractory epilepsy is still difficult, and little is known about its mechanisms, especially about homeostasis synaptic plasticity. The ability of neurons and circuits to maintain their excitability and activity levels within the appropriate dynamic range by homeostatic mechanisms is fundamental for brain function. One such homeostatic process is synaptic scaling, also known as synaptic homeostasis. It involves a negative feedback process by which neurons adjust (scale) their postsynaptic strength over their whole synapse population to compensate for increased or decreased overall input thereby preventing neuronal hyper- or hypoactivity that could otherwise result in neuronal network dysfunction. The role of glial transmitters in regulating neurons has attracted increasing attention. Previous studies have confirmed that knockout of astrocytic Lrp4 leads to decreased excitatory input of hippocampal neurons, which inevitably leads to changes in homeostasis synaptic plasticity. Our preliminary studies have found that astrocytic Lrp4 participates in the genesis of drug-resistant epilepsy by regulating homeostasis synaptic plasticity. On this basis, this study aims to explore the role of Lrp4 in the genesis of drug-resistant epilepsy, including the temporal and spatial changes of Lrp4 expression in the brain, the effects of knockout or overexpression of Lrp4 on the occurrence and development of drug-resistant epilepsy; and the role of Lrp4 in mediating drug-resistant epilepsy by regulating homeostasis synaptic plasticity, including the effects of astrocytic Lrp4 on homeostasis synaptic plasticity, Lrp4-mediated occurrence of drug-resistant epilepsy by regulating the homeostasis of synaptic plasticity and its molecular mechanisms. Our results would be beneficial to elucidate the role of astrocytic Lrp4 in the pathogenesis of drug-resistant epilepsy and its homeostasis-synaptic-plasticity regulation mechanism, so as to provide new ideas and targets for the prevention and treatment of drug-resistant/refractory epilepsy.

目前对耐药性/难治性癫痫的治疗仍是难点，对其机制特别是在自身稳态的突触可塑性方面仍知之甚少。“胶质递质”调控神经元的作用日趋受到关注。以往研究证实敲除星形胶质细胞Lrp4导致海马神经元兴奋性输入减弱，势必引起自身稳态突触可塑性改变；我们前期研究发现星形胶质细胞Lrp4通过调控自身稳态突触可塑性参与耐药性癫痫的发生。在此基础上，本项目拟首先探明星形胶质细胞Lrp4在耐药性癫痫发生中的作用，包括Lrp4表达的时空变化、敲除或过表达Lrp4对耐药性癫痫发生、发展的影响；其次研究星形胶质细胞Lrp4通过调控自身稳态突触可塑性介导耐药性癫痫发生的作用，包括Lrp4对自身稳态突触可塑性的影响、星形胶质细胞Lrp4通过调控自身稳态的突触可塑性介导耐药性癫痫的发生及其分子机制。有望阐明星形胶质细胞Lrp4在耐药性癫痫发病中的作用及其“自身稳态”突触可塑性调控机制，为防治耐药/难治性癫痫提供新思路、新靶点。

目前对耐药性/难治性癫痫的治疗仍是难点，对其机制特别是在自身稳态的突触可塑性方面仍知之甚少。“胶质递质”调控神经元的作用日趋受到关注。以往研究证实敲除星形胶质细胞Lrp4导致海马神经元兴奋性输入减弱，势必引起自身稳态突触可塑性改变。本项目基本明确星形胶质细胞Lrp4 在耐药性癫痫发生中的作用：观察了耐药性癫痫（DRE）模型星形胶质细胞Lrp4 在不同脑区、不同时间点的表达水平和变化特点；探讨了敲除星形胶质细胞Lrp4 对耐药性癫痫的发生、发展的影响。基本探明星形胶质细胞Lrp4 通过调控自身稳态的突触可塑性介导耐药性癫痫的发生：首先检测星形胶质细胞Lrp4 敲除DRE模型海马或其它脑区自身稳态的突触可塑性的强弱及动态变化特点；其次结合药理学或分子生物学手段干预特定脑区的自身稳态的突触可塑性，观察其对星形胶质细胞Lrp4 敲除DRE模型行为学和电生理特性的影响。同时观察Lrp4 上下游分子的磷酸化、蛋白表达水平的变化。研究结果有望阐明星形胶质细胞Lrp4 在耐药性癫痫发病中的作用及其“自身稳态”突触可塑性调控机制，为防治耐药/难治性癫痫提供新思路，为早期干预提供新靶点。研究成果目标基本完成。目前已发表SCI论文2篇（第三标注），1篇英文论文投稿中（第一标注），1篇英文论文撰稿中（第一标注），协助培养研究生2名。并完成一定的学术交流目标。