Nogo-A在PTSD大鼠海马突触改变及靶向免疫治疗中的作用与机制研究

Posttraumatic stress disorder (PTSD), as a kind of learning and memory disorder disease, its occurrence is closely related to the changes of hippocampal synaptic plasticity. Recent studies show that, as an important myelin inhibitory factor, the inhibitory effect of Nogo-A mediated by two important functional domains including Nogo-66 and NogoΔ20, can not only be involved in the regeneration of central nervous system after injury, but also mediated synaptic plasticity changes of hippocampal neurons through its downstream signal pathway. Thus, it is seemed that Nogo-A may regulate hippocampal synaptic plasticity through the two important functional domains, and mediated the pathology of PTSD. In order to prove the hypothesis and discuss the feasibility of immunotherapy targeted Nogo-A for PTSD, based on our previous studies, this study firstly construct the eukaryotic expression vector encoding Nogo-66, Amino-Nogo (containing NogoΔ20) and GM-CSF, the animals were immunized by using the vector together with liposome or gold nanoparticles, then behavioral detection methods, such as the open field test, elevated plus maze and water maze were used to detect its therapeutic effect on PTSD, and further observe and explore the effects and possible mechanisms of Nogo-A on synaptic plasticity in hippocampal neurons. This study is sure to provide new therapeutic targets and strategies for the treatment of PTSD as well as other mental disorders.

创伤后应激障碍(PTSD)作为一种学习和记忆障碍类疾病，其发生与海马突触可塑性改变密切相关。近年研究表明，作为一种重要的髓磷脂抑制因子，Nogo-A不仅可通过其两个重要功能域Nogo-66和NogoΔ20参与中枢神经损伤后再生的抑制效应，还可通过其下游信号通路介导海马神经元突触可塑性改变，因此推断Nogo-A可能通过调节海马突触可塑性介导PTSD的发生。为证实该假说并初步探讨以Nogo-A作为靶点，对PTSD进行免疫治疗的可行性，本研究在前期研究的基础上首先构建共表达Nogo-66、Amino-Nogo(含NogoΔ20)及GM-CSF的真核表达载体，与脂质体或纳米金一起免疫动物，采用旷场实验、高架十字迷宫及水迷宫等行为学检测方法观察其对PTSD大鼠的免疫治疗作用并初步探讨Nogo-A对海马神经元突触可塑性的影响及可能的作用机制，为PTSD及其他精神障碍提供新的治疗靶点和治疗策略。

创伤后应激障碍(PTSD)作为一种学习和记忆障碍类疾病，其发生与海马突触可塑性改变密切相关。近年研究表明，作为一种重要的髓磷脂抑制因子，Nogo-A不仅可通过其两个重要功能域Nogo-66和NogoΔ20参与中枢神经损伤后再生的抑制效应，还可通过其下游信号通路介导海马神经元突触可塑性改变，因此推断Nogo-A可能通过调节海马突触可塑性介导PTSD的发生。为证实该假说并初步探讨以Nogo-A作为靶点，对PTSD进行免疫治疗的可行性，本研究在前期研究的基础上首先构建了共表达Nogo-66、Amino-Nogo(含NogoΔ20)及GM-CSF的真核表达载体，与脂质体（Liposomes）或纳米金（GNPs）一起免疫动物，采用旷场实验、高架十字迷宫及水迷宫等行为学检测方法观察其对PTSD大鼠的免疫治疗作用并初步探讨Nogo-A对海马神经元突触可塑性的影响及可能的作用机制，为PTSD及其他精神障碍提供新的治疗靶点和治疗策略。结果表明，成功构建了共表达Nogo-66、Amino-Nogo(含NogoΔ20)及GM-CSF的GMCSF-Nogo真核表达载体，并在此基础上经脂质体或纳米金包被后成功制备了高效价的Nogo-A靶向核酸疫苗。Nogo-A靶向核酸疫苗免疫PTSD大鼠对其行为学有一定的改善效应，能有效改善海马神经元的数量和形态，增加轴突、树突数量及复杂性，提高树突棘的密度。其机制可能是核酸疫苗免疫产生的Nogo-A抗体有效逆转了内源性Nogo-A及其下游信号通路介导的海马神经元突触可塑性的不利影响，上调Synapsin I、p-CREB的表达，促进海马神经元突触可塑性来实现的。该研究为PTSD及其它中枢神经疾病的药物研发提供新的方法和理论依据。