Behavioural Neuroscience Laboratory, Department of Experimental Medical Sciences, Lund University, Lund, Sweden.
Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ, USA.
Behav Brain Res. 2022 Jul 5;429:113887. doi: 10.1016/j.bbr.2022.113887. Epub 2022 Apr 8.
Preclinical rodent models of Parkinson's aim to recapitulate some of the hallmarks of the disease as it presents in humans, including the progressive neuronal loss of dopaminergic neurons in the midbrain as well as the development of a behavioral phenotype. AAV vector-based models of alpha-synuclein overexpression are a promising tool to achieve such animal models with high face and predictive validity.
We have developed a preclinical rodent model of Parkinson's disease using an AAV-vector based overexpression of human alpha-synuclein. In the present work we characterize this model on a behavioral and histopathological level.
We use a AAV9 vector for transgene delivery to overexpress human alpha-synuclein under a CBA promoter. We compare the behavioral and histopathological changes to a AAV vector control group where the transgene was omitted and to that of a 6-OHDA lesion control. We assessed the behavioral performance of these three groups on a series of tests (Cylinder, Stepping, Corridor) at baseline and up to 22 weeks post-injection at which point we performed electrochemical recordings of dopamine kinetics.
The overexpression of human alpha-synuclein led to the progressive manifestation of behavioral deficits on all three behavioral tests. This was accompanied with impaired dopamine release and reuptake kinetics as demonstrated by electrochemical detection methods. Histopathological quantifications corroborated the findings that we induced a moderate cell loss with remaining cells displaying pathological markers which are abundant in the brains of human PD patients.
In the present work we developed a characterized a rat model of PD that closely mimics human disease development and pathology. Such model will be of great use for investigation of disease mechanisms and early therapeutic interventions.
帕金森病的临床前啮齿动物模型旨在再现人类疾病的一些特征，包括中脑多巴胺能神经元的进行性丧失以及行为表型的发展。过表达α-突触核蛋白的 AAV 载体模型是实现具有高表面和预测效度的动物模型的有前途的工具。
我们使用基于 AAV 载体的人α-突触核蛋白过表达开发了帕金森病的临床前啮齿动物模型。在本工作中，我们在行为和组织病理学水平上对该模型进行了表征。
我们使用 AAV9 载体进行转基因传递，以 CBA 启动子过表达人α-突触核蛋白。我们将行为和组织病理学变化与 AAV 载体对照组（省略了转基因）和 6-OHDA 损伤对照组进行比较。我们在基线和注射后 22 周对这三组进行了一系列测试（圆筒、踏步、走廊），在此期间，我们通过电化学检测方法记录多巴胺动力学。
人α-突触核蛋白的过表达导致所有三种行为测试的行为缺陷逐渐出现。这伴随着多巴胺释放和再摄取动力学的受损，电化学检测方法证明了这一点。组织病理学定量证实了我们诱导了适度的细胞丢失，剩余的细胞显示出在人类 PD 患者大脑中大量存在的病理标志物。
在本工作中，我们开发了一种与人帕金森病发展和病理学密切相似的大鼠模型。这种模型将非常有助于研究疾病机制和早期治疗干预。
