5-HT3受体调控空间学习记忆的突触及分子机制研究

Cognitive dysfunction is one of the major symptoms and an unsolved problem in a variety of neurological and psychiatric disorders. Previous studies on the mechanisms of cognitive function and memory have been mainly focused on the excitatory glutamatergic synaptic transmission and the modulation of cholinergic neurotransmitter. While modulators of cholinergic system are widely used for the treatment of cognitive impairment in these diseases, there is still high clinically unmet need for novel medications that can overcome the limitations of current therapies. More recent investigations demonstrate that inhibitory synapses also play critical roles in neural circuit refinement and learning. Growing evidence that emerged indicate that the modulators of serotonin system and its receptors may improve cognition in AD and PD patient. 5-HT3 receptors (5-HT3Rs), the only ligand-gated cation channels in 5-HT receptor family, are specifically expressed in GABAergic interneurons in the hippocampus and mediate fast synaptic transmission in these RH-IN synapses. However, less is known about the role of 5-HT3Rs in memory and the underlying mechanisms. In this study, on the basis of our preliminary data, using 5-HT3AR KO and GFP mouse lines, we will determine the physiological roles of 5-HT3Rs in spatial memory and its synaptic as well as neuronal network mechanisms. Additionally, we will investigate a novel CB1R-GABA-dependent pathway by which 5-HT3Rs regulate spatial memory. We will systematically and deeply explore the function of 5-HT3Rs on behavioral-slice- cellular- synaptic-molecular levels. Our results will facilitate the understanding of neuronal mechanisms in regulation of learning and memory, which may have implications for using 5-HT3R modulators in treatment of cognitive disorders.

认知障碍疾病始终是有待解决的重要问题，以往记忆机制研究多集中在兴奋性突触及胆碱能递质的调控，认知障碍药物治疗也主要集中在胆碱酯酶抑制剂、MNDA受体拮抗剂等，但疗效有限。最近研究表明，抑制性突触在记忆中也起了重要作用，而5-HT受体调节剂能改善AD等的记忆障碍。5-HT3受体是5-HT受体中唯一的阳离子通道受体，在海马特异表达在抑制性中间神经元上，介导中缝核-海马中间神经元的快速突触传递。但5-HT3受体在记忆中的作用机制还有待阐明。本课题将运用5-HT3A受体KO及GFP小鼠，明确5-HT3受体在空间记忆中的作用，研究该受体对突触可塑性调节的机制，并探讨一条新的CB1R-GABA依赖通路在其中的作用。我们将在整体-脑片-细胞-突触-分子水平系统又深入地研究5-HT3受体在记忆中的作用机制。研究结果将有助于完善记忆调节神经机制的认识，可能为运用5-HT3受体调节剂治疗认知障碍疾病提供帮助。

认知障碍疾病始终是有待解决的重要问题，以往记忆机制研究多集中在兴奋性突触及胆碱能递质的调控，认知障碍药物治疗也主要集中在胆碱酯酶抑制剂、MNDA受体拮抗剂等，但疗效有限。最近研究表明，抑制性突触在记忆中也起了重要作用，而5-HT受体调节剂能改善AD等的记忆障碍。5-HT3受体是5-HT受体中唯一的阳离子通道受体，在海马特异表达在抑制性中间神经元上，介导中缝核-海马中间神经元的快速突触传递。但5-HT3受体在记忆中的作用机制还有待阐明。本课题运用5-HT3A受体KO及GFP小鼠，明确了5-HT3受体在空间记忆中的作用，发现5-HT3Rs基因敲除通过易化锥体神经元GABA能的传入损害海马LTP和空间记忆。5-HT3Rs敲除通过下调与其共表达在CCK/VIP中间神经元上的CB1受体的表达和功能实现GABA释放的去抑制，使GABA释放增加，抑制增强而抑制LTP和空间记忆。本研究证实了5-HT3受体通过CB1R-GABA依赖通路调节突触可塑性和空间记忆的机制，研究结果将有助于完善记忆调节神经机制的认识，可能为运用5-HT3受体调节剂治疗认知障碍疾病提供帮助。