Department of Neurobiology, Department of Physiology and Pathophysiology, Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China.
Theranostics. 2021 Mar 4;11(10):4616-4636. doi: 10.7150/thno.54210. eCollection 2021.
Poststroke cognitive impairments are common in stroke survivors, and pose a high risk of incident dementia. However, the cause of these cognitive impairments is obscure and required an investigation. Oxygen-glucose deprivation (OGD) model and middle cerebral artery occlusion (MCAO) model were used to imitate or acute cerebral ischemia, respectively. The differentially expressed synaptosome associated protein 29 (SNAP29)-interacting proteins upon ischemia and reperfusion were analyzed with bioinformatics analysis and the results indicated that the changes of SNAP29 after acute ischemia were mainly involved in the synaptic functions. The outcomes of SNAP29 reduction were assessed with SNAP29 knockdown, which mimicked the distribution of SNAP29 along neuronal processes after acute ischemia. Using the whole-cell patch clamp recording method and transmission electron microscope, the pre-synaptic function and readily releasable pool (RRP) were observed after SNAP29 knock down. Using photogenetic manipulations and behavioral tests, the neuronal projection and cognitive functions of mice with SNAP29 knock down in hippocampus CA1 region were evaluated. It was found that SNAP29 protein levels decreased in both and ischemic models. Further, the SNAP29 reduction wasn't associated with impaired autophagy flux and neuronal survival. When SNAP29 was knocked down in primary cortical neurons, the frequency of AMPARs-mediated mEPSCs, but not the amplitude, significantly decreased. Meanwhile, the mice with SNAP29 knockdown at CA1 region of hippocampus developed an impairment in hippocampus-mPFC (middle prefrontal cortex) circuit and behavioral dysfunctions. Moreover, the size of RRP at presynaptic sites was diminished. Since SNAP29 protein levels didn't significantly influence the neuronal survival and its decrease was sufficient to disturb the neural circuit via a presynaptic manner, the SNAP29-associated strategies may be an efficient target against poststroke synaptic dysfunction and cognitive deficits.
卒中后认知障碍在卒中幸存者中很常见，并且是发生痴呆的高风险因素。然而，这些认知障碍的原因尚不清楚，需要进行研究。 氧葡萄糖剥夺（OGD）模型和大脑中动脉闭塞（MCAO）模型分别用于模拟急性脑缺血。通过生物信息学分析分析了缺血再灌注后突触体相关蛋白 29（SNAP29）相互作用蛋白的差异表达，结果表明急性缺血后 SNAP29 的变化主要涉及突触功能。通过 SNAP29 敲低评估 SNAP29 减少的结果，这模拟了急性缺血后 SNAP29 在神经元过程中的分布。使用全细胞膜片钳记录方法和透射电子显微镜观察 SNAP29 敲低后突触前功能和易释放池（RRP）。使用光遗传操作和行为测试评估海马 CA1 区 SNAP29 敲低的小鼠的神经元投射和认知功能。结果发现，和缺血模型中 SNAP29 蛋白水平均降低。此外，SNAP29 减少与自噬通量和神经元存活无关。当 SNAP29 在原代皮质神经元中被敲低时， AMPAR 介导的 mEPSC 的频率显着降低，但幅度没有变化。同时，海马 CA1 区 SNAP29 敲低的小鼠在海马 - mPFC（中前额叶皮层）回路中表现出损伤和行为功能障碍。此外，突触前部位的 RRP 大小减小。由于 SNAP29 蛋白水平对神经元存活没有显着影响，并且其减少足以通过突触前方式干扰神经回路，因此 SNAP29 相关策略可能是针对卒中后突触功能障碍和认知缺陷的有效靶点。
