酸敏感离子通道调节突触传递和可塑性的机制研究

神经系统中突触传递及其可塑性被认为是学习和认知的基础，同时异常可塑性广泛参与常见和重大脑疾病发生和发展过程。离子通道作为膜电位的承担者和动作电位的介导者，其表达和功能的变化直接影响神经元兴奋性调节和可塑性形成。酸敏感离子通道（ASIC）是一类可被质子激活的新型阳离子通道。近年来发现其与学习记忆，感觉和运动障碍等生理病理过程密切相关，因此ASIC参与中枢神经可塑性的研究是当前神经可塑性和离子通道领域的前沿方向之一。申请人等长期研究ASIC的结构、功能与调控，发现ASIC参与脊髓痛觉可塑性和缺血性海马神经元损伤等病理过程。本项目旨在这些前期工作基础上，综合运用电生理学，生化与分子生物学，细胞生物学，转基因动物与疾病模型等多种技术手段，深入研究ASIC调节突触传递与神经可塑性的机理，阐述ASIC和神经可塑性的生理和病理意义，并为开展以ASIC为靶标，针对异常神经可塑性的疾病干预提供理论依据。

Synaptic transmission and its plasticity are proposed as the cellular and molecular basis of learning and memory, and dysregulation of synaptic plasticity contributes to many neural disorders. Ion channels, which underlie the membrane potential and mediate action potential, play essential roles in neuronal excitability and synaptic plasticity. Acid-sensing ion channel (ASIC) represents a new family of non-selective cation channels activated by extracellular protons. Much evidence from our own and others implicate ASIC in a variety of physiological (such as learning and memory) and pathological conditions (such as cell injury and pain). In particular, we have previously demonstrated that ASIC contributes to the ischemic hippocampal neuron death (Neuron, 2005) and spinal central sensitization associated with inflammatory pain (JNS, 2007; 2012; Prog. Neurobiol, 2009). The mechanism and signaling pathway of the involvement of ASIC in synaptic plasticity remain unexplored. In this proposal, we are going to use ASIC gene knockout mice, viral-genetics and electrophysiological recordings in combinations with disease models to study the cellular and molecular mechanisms underlying ASIC regulation of synaptic plasticity. These studies are expected to reveal the physiological significance of ASIC channels and synaptic plasticity. By manipulating ASIC expression, trafficking and function, this research may also provide the foundation for exploring novel therapeutics against aberrant neural plasticity associated with ASIC dysregulation.