小胶质细胞源性IL-1β通过SSH1/Cofilin调控突触可塑性介导抑郁症发病的机制研究

Recently, neuroinflammation is considered as an important factor leading to brain dysfunction in depression. The current anti-inflammatory drug has more side effects which inadequate for antidepression therapies. We have investigated and reported the important role of synaptic plasticity in the infralimbic cortex of prefrontal cortex in chronic unpredicted mild stress induced depression animal model. Recently, we found that the activated microglia and the level of inflammatory factor such as IL-1β is increased and involved in the neuronal synaptic plasticity in chronic stressed rats, while knockdown IL-1β could improve synaptic plasticity, and thus ameliorated the depression-like behaviors. Further study found that overexpression of IL-1β activated cofilin which associated with synaptic plasticity while companied with decreased EPSC and induction of LTD. These results suggested that IL-1β may contribute to the induction of depression via modulating neuronal synaptic plasticity. Therefore, based on the previous findings, we will use virus injection, optogenetics and Cre-loxp conditional gene knockout methods to further investigate the following aspects: (1) investigate the role of IL-1β signaling pathway on the function of neuronal circuit and the mechanism of IL-1β on regulating the neuronal plasticity; (2) illustrate the mechanisms by which IL-1β signaling pathway could contribute to the synaptic plasticity in vivo and as well as depression-like disorders in chronic stress induced depressive rats. Controlling the expression of this pathway could improve mental disorders therapy and provide the new target for drug discovery and development.

最近临床证据表明，神经炎症是抑郁症的易感因素，但机制不清。且目前的抗炎药物副作用大，不适于抗抑郁长期治疗。申请人前期研究发现，抑郁症大鼠内侧前额叶皮质（mPFC）小胶质细胞激活，炎症因子IL-1β表达增加。进一步研究发现神经元成熟树突棘比例降低、突触数量减少，并伴随切丝蛋白Cofilin的激活；电生理结果显示神经元兴奋性突触后电流幅度降低，呈长时程压抑。而敲减mPFC区的IL-1β或阻断其受体均有显著的抗抑郁作用。以上结果表明IL-1β可能通过调控神经元突触可塑性而介导抑郁症的发生。因此本项目拟利用膜片钳、光遗传调控及Cre-loxp条件性基因敲除等技术，结合分子生物学和行为检测等方法，研究：1）IL-1β调控神经元突触可塑性的神经及分子机制；2）IL-1β调控神经元突触可塑性在抑郁症发病中的作用。从而阐明神经炎症介导抑郁症发病的机理，为抑郁症的抗炎治疗策略提供新的药物靶点和理论依据。

抑郁症主要表现为持续的情绪低落、思维迟缓、甚至绝望自杀等情感和行为障碍，严重影响生存质量，但其病理机制复杂，迄今尚未彻底阐明。目前已有的临床治疗药物主要针对脑内单胺类递质系统的失衡，但起效慢、副作用大、易复发，提示抑郁症可能还有其它更为复杂的生物学发病机制。中枢神经系统(CNS)的炎症过程与包括抑郁症在内的多种神经系统疾病相关，神经炎症是抑郁症的易感因素，但炎症介导的神经元损伤及抑郁样行为的机制，尤其是抑制炎症可否作为抑郁症治疗的潜在策略，目前仍不清楚。本项目旨在探究炎症导致抑郁大鼠模型神经元损伤的神经机制和信号通路，从而确定具有潜在抗抑郁治疗作用的药物。研究结果发现慢性不可预知性温和应激(CUMS)诱导内侧前额叶皮质(mPFC)内的小胶质细胞活化和细胞因子白细胞介素-1β (IL-1β)、白细胞介素-6 (IL-6)和肿瘤坏死因子-α (TNF-α)的过度表达。给予IL-1β或核因子κB (NF-κB)拮抗剂可显著改善神经结构和生化指标的失调，如SSH1和磷酸化丝切蛋白以及由CUMS暴露引起的抑郁样行为的表现。进一步研究发现抑郁大鼠神经元成熟树突棘比例降低、突触数量减少，并伴随切丝蛋白Cofilin的激活；而敲减mPFC区的IL-1β或阻断其受体均有显著的神经保护及抗抑郁作用。此外，本研究亦发现姜黄素预处理(40 mg/kg，腹腔注射，5周)可有效发挥抗抑郁的作用，并抑制炎症反应和神经元结构的异常。以上结果表明IL-1β可能通过调控神经元突触可塑性而介导抑郁症的发生。这些发现揭示了与抑郁症相关的神经炎症分子通路，即IL-1β调控神经元突触可塑性的神经及分子机制；以及IL-1β调控神经元突触可塑性在抑郁症发病中的作用。本研究阐明了神经炎症介导抑郁症发病的机理，并为开发潜在的抗抑郁治疗中与炎症相关的新的药物靶点提供了新的理论依据和研究途径。