岛叶皮层突触可塑性的非经典离子通道机制

Insular cortex is an important forebrain structure involved in several sensory and cognitive functions and dysfunctions, such as pain perception, taste memory, self-awareness and drug addiction. Our previous work shows that insular synapses could undergo typical forms of synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD), which might set the synaptic basis for the above behaviors mediated by the insular cortex. However, the detailed signaling pathways underlying insular synaptic plasticity are still not clear. The acid-sensing ion channels (ASICs) are widely expressed in the CNS, and there is evidence indicating that ASIC1a has a role in hippocampal LTP. However, no information is available on the contribution of ASIC1a to insular synaptic transmission and plasticity. The present project was aimed to address this issue through a combination of several neurobiological techniques, such as patch-clamp, multi-electrode array recording, viral genetics, genetically-engineered mice, biochemistry and molecular biology. Specifically, we will focus on the following four research contents: (1) expression and distribution of ASICs in the insular cortex; (2) effects of ASIC1a on basal synaptic efficacy and intrinsic excitability; (3) roles of ASIC1a in multiple forms of insular synaptic plasticity; (4) signaling mechanisms underlying the ASIC1a-dependent insular plasticity. These studies are expected to shed novel insights into the precise ionic mechanisms of synaptic plasticity in the insular cortex, as well as providing the molecular explanation on the physiological functions of ASICs.

岛叶皮层是哺乳动物脑内一个重要结构，参与诸多生理功能和疾病过程。申请人长期致力于岛叶皮层突触可塑性研究，率先在成年小鼠的岛叶皮层成功诱导长时程增强（LTP）和长时程抑制（LTD），但这些突触可塑性的形成机制和功能意义有待进一步研究。酸敏感离子通道（ASIC）是一类由胞外质子激活的阳离子通道，在大脑皮层高表达，并且已有证据表明ASIC亚基1a基因敲除损害海马皮层LTP，但ASIC1a是否以及如何影响岛叶皮层LTP和LTD尚未见文献报道。本项目拟运用常规和岛叶皮层条件性基因敲除、药理学、病毒携带基因干预/解救、脑片膜片钳、离体多通道阵列记录分析、生物化学与分子生物学等多种技术手段，研究ASIC在岛叶皮层的表达定位及其对岛叶基础突触传递以及突触可塑性的影响，并揭示ASIC1a贡献岛叶突触可塑性的分子机制,为进一步阐明岛叶突触可塑性的发生机理提供新思路,也为加深理解ASIC的生理功能提供新依据。

岛叶皮层作为哺乳动物体内一个非常重要的结构已被报道参与调节诸多机体的生理功能，如疼痛感受，味觉记忆的形成储存，以及自我意识等等。但岛叶参与这些行为过程的突触基础和细胞分子机制仍不清楚。酸敏感离子通道（ASIC）是一类由质子激活的非选择性阳离子通道。大量前人研究集中在探索ASIC在各类神经系统疾病发生发展中的作用。但相比之下，该通道的突触生理功能研究较少。本项目综合运用脑片膜片钳、离体多通道阵列记录分析、分子遗传学、生物化学与细胞生物学、急性病毒在体干预、行为学等多学科交叉实验手段，围绕岛叶皮层突触可塑性的非经典离子通道机制这一核心问题，深入系统地研究了ASIC1a亚基在岛叶皮层的表达及其对基础突触传递和各类突触可塑性现象的影响，揭示了ASIC1a调控岛叶LTD的详细分子机制，阐明了ASIC1a介导的LTD在味觉厌恶记忆消退过程中的关键作用。另外，项目组还拓展研究了ASIC1a在海马和前扣带回皮层的突触可塑性中的贡献及其可能的工作机制和病理生理意义。上述研究结果有助于加深理解岛叶突触可塑性的新机制，也丰富了ASIC1a突触功能的理论框架。本项目已在《Nature Communications》、《Scientific Reports》、《Neuropharmacology》等国际学术期刊发表论文3篇，申请中国发明专利1项，协助培养博士研究生3名。项目组成员共参加国内外学术会议5人次，圆满完成了预期目标。