α7烟碱型乙酰胆碱受体对胶质传递的作用及其与帕金森病的相关性研究

Astrocytes are the most abundant glial cells in the central nervous system (CNS) of mammals. Although astrocytes are not electrically excitable, they have been shown to function as active participants in neural circuits and synaptic activity. Astrocytes respond to neurotransmitters and contribute to synaptic information processing by releasing chemical transmitters called “gliotransmitters.” Recent studies have demonstrated that the disruption of gliotransmission results in neuronal dysfunction and neurodegenerative disease, including Parkinson’s disease (PD). Accumulating evidence suggests that CNS α7 nicotinic acetylcholine receptors (nAChRs) are important targets for the development of therapeutic approaches for PD. However, little is known about the role of α7-nAChRs in the regulation of astrocyte gliotransmission. Thus, we hypothesize that astroglial α7-nAChRs may contribute to PD by directly regulating the gliotransmission. Here, using α7-nAChRs knockout mice, we first determined whether α7-nAChRs regulates the release of gliotransmitters, such as ATP, D-serine, and L-glutamate, when introduced into mice by stereotaxic injections or transfection. Furthermore, primary astrocyte culture from adult or neonatal mice are used to study the cellular mechanism of α7-nAChRs underlying the gliotransmission. These findings will demonstrate that glial α7-nAChRs regulates the release of gliotransmitters and plays a protective role in the physiology and pathophysiology of PD. We also suggest that regulating the function of glial α7-nAChRs by gene therapeutic and/or pharmacological means should be a potential target for the treatment of PD.

星形胶质细胞是神经胶质细胞的主要组成成分，广泛参与脑内神经发生的各个环节。目前缺少特异性调节星形胶质细胞胶质传递功能的靶点，制约了神经保护治疗学的突破，成为研发理想药物的瓶颈。α7 nAChRs是治疗PD的重要调控靶点，进一步研究α7 nAChRs调节星形胶质细胞胶质传递的机制对于揭示α7 nAChRs的神经保护机制、探索PD治疗新策略具有重大意义。因此，我们提出：α7 nAChR通过调节星形胶质细胞的胶质传递功能，介导神经网络的corsstalk，从而保护神经元。为了验证这一假说，在α7 nAChRs敲除小鼠的基础上，从整体、细胞和分子水平研究PD模型中α7 nAChRs与星形胶质细胞介导的胶质传递之间的相关性，并阐明其机制，为基于星形胶质细胞的神经保护治疗和药物研发提供新靶标。

近年来研究表明α7-nAChRs通过对脑内星形胶质细胞功能的调节在帕金森病的发展中发挥重要作用。本项目主要应用α7-nAChRs 敲除小鼠制备慢性PD模型，首先阐明α7-nAChRs调节胶质细胞功能与多巴胺能神经退行性变的相关性，进一步发现激动α7-nAChRs不仅可以通过ERK MAPK/p53信号通路减轻MPP+诱导的SH-SY5Y细胞凋亡，还可通过JNK/p53抑制原代星形胶质细胞的凋亡、维持其营养支持功能。这些研究结果揭示激动α7-nAChRs可成为靶向于神经元-胶质细胞网络的新型神经保护策略。