mTOR信号激活KATP通道而调控皮层L5爆发式放电神经元的活动及其在运动发育学习中的作用

Mammalian target of rapamycin (mTOR) is a serine / threonine protein kinase, mediating intracellular signal transduction, while ATP-sensitive potassium (KATP) channel is a membrane channel protein sensing the metabolic state of a cell to its electrical activity, both of which have many important neural regulatory effects. In recent years, increasing evidence shows that the activation of KATP channels could promote the cross-talks among multiple intracellular signaling pathways. It has been demonstrated that the mTOR signaling increase the activity of KATP channels to inhibit the electrical activity of the hypothalamic POMC neuron. Motor cortex deep layer such as L5 pyramidal neurons play a key role in the motor development and motor learning. As most of the L5 pyramidal neurons develop as the burst spiking (BS) neurons in the mature brain, its relationship to the motor development and motor learn ability is not clear. We plan to selectively interfere with mTOR-KATP pathway of the L5 neurons, applying tools of molecular biology, electrophysiology, morphology and behavioral assessments to reveal ① mTOR-KATP pathway expressions correlate to the electrophysiological properties of the BS neurons in an age-dependent manner; ②mTOR-KATP pathway mediates the electrical discharge characteristics of the BS neurons; ③The regulatary molecular mechanisms underline the effects of mTOR-KATP pathway on a BS neuron; ④mTOR-KATP pathway's regulation on electrophysiological properties of the BS neurons controls the motor development and motor learning ability. Our findings will deepen the understanding of the mTOR-KATP pathway in regulating the neuronal activity and the brain function, particularly for the understanding of the neurobiological mechanisms of motor development and motor learning ability.

雷帕霉素靶蛋白（mTOR）是一种丝/苏氨酸蛋白激酶，介导细胞内信号转导，而ATP敏感钾（KATP）通道是内向整流钾离子通道，两者均具有诸多重要的神经调节功能。近年发现激活KATP通道能促进细胞内多种信号通路的交互作用。已有证据显示mTOR信号通过提高KATP通道活动而抑制下丘脑POMC神经元的活动。皮层运动区深层L5锥体神经元在运动学习中起着关键作用，成熟后多数成为爆发式放电（BS）类型，这种特征与运动发育学习的关系不明确。我们拟选择性地干扰L5神经元mTOR-KATP途径，综合应用分子生物学、电生理学、形态学和行为学等多种研究手段，以揭示mTOR信号与KATP通道的相互作用及机制，明确其年龄依赖性地调控BS神经元爆发式放电的特性，及其对运动发育学习能力的调控作用。研究结果将有助于人们更好了解mTOR-KATP途径对脑功能活动的调节作用、了解运动发育学习能力的神经生物学机制和意义。

雷帕霉素靶蛋白（mTOR）是一种丝/苏氨酸蛋白激酶，介导细胞内信号转导，而ATP敏感钾 （KATP）通道是内向整流钾离子通道，两者均具有诸多重要的神经调节功能。近年发现激 活KATP通道能促进细胞内多种信号通路的交互作用。已有证据显示mTOR信号通过提高KATP 通道活动而抑制下丘脑POMC神经元的活动。皮层运动区深层L5锥体神经元在运动学习中起 着关键作用，成熟后多数成为爆发式放电（BS）类型，这种特征与运动发育学习的关系不 明确。我们拟选择性地干扰L5神经元mTOR-KATP途径，综合应用分子生物学、电生理学、 形态学和行为学等多种研究手段，以揭示1）mTOR-KATP途径和BS神经元电生理特性的年龄依赖性及其之间的相关性；2）mTOR-KATP途径对BS神经元爆发式放电特性的决定作用；3）mTOR-KATP途径对BS神经元电生理特性调控的分子机制。研究结果将有助于人们更好了解mTOR-KATP途径对脑功能活动的调节作用、了解运动发育学 习能力的神经生物学机制和意义。我们已在国际神经科学界的权威期刊发表至少3篇论文，2篇影响因子＞3分（已标注）。在相关研究方向上已培养研究生2 名。我们与以往合作者Indiana大学Xiaoming Jin（金小明）助理教授及其实验室间开展了深入的学术交流活动。课题主持人前往美国罗马林达儿童医院进行学术交流2个月，方向是儿童神经精神发育异常的评估与诊治。今后将继续加强在体行为学方面的深入研究、加强成果的转化和应用。