Induction of Parkinsonian-Like Changes via Targeted Downregulation of Astrocytic Glutamate Transporter GLT-1 in the Striatum

Article type: Research Article

Authors: Ren, Chao^{a; b; c; 1} | He, Kai-Jie^{b; 1} | Hu, Hua^{a; 1} | Zhang, Jin-Bao^{a; b} | Dong, Li-Guo^{a; b} | Li, Dan^d | Chen, Jing^a | Mao, Cheng-Jie^a | Wang, Fen^{a; b; *} | Liu, Chun-Feng^{a; b; d; e; *}

Affiliations: [a] Department of Neurology and Clinical Research Center of Neurological Disease, the Second Affiliated Hospital of Soochow University, Suzhou, China | [b] Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China | [c] Department of Neurology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China | [d] Department of Neurology, Suqian First Hospital, Suqian, China | [e] Department of Neurology, The Second Affiliated Hospital of Xinjiang Medical University, Urumqi, China

Correspondence: [*] Correspondence to: Chun-Feng Liu, Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou 215004, China. E-mail: [email protected].; Fen Wang, Institute of Neuroscience, Soochow University, 199 Renai Road, Suzhou 215123, China. E-mail: wangfen [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Background:Previous investigations have suggested that decreased expression of glutamate transporter-1 (GLT-1) is involved in glutamate excitotoxicity and contribute to the development of Parkinson’s disease (PD), GLT-1 is decreased in animal models of PD. GLT-1 is mainly expressed in astrocytes, and the striatum is a GLT-1-rich brain area. Objective:The aim was to explore the function and mechanism of astrocytic GLT-1 in PD-like changes. Methods:In the study, PD-like changes and their molecular mechanism in rodents were tested by a behavioral assessment, micro-positron emission tomography/computed tomography (PET/CT), western blotting, immunohistochemical and immunofluorescence staining, and high performance liquid chromatography pre-column derivatization with O-pthaldialdehida after downregulating astrocytic GLT-1 in vivo and in vitro. Results:In vivo, after 6 weeks of brain stereotactic injection of adeno-associated virus into the striatum, rats in the astrocytic GLT-1 knockdown group showed poorer motor performance, abnormal gait, and depression-like feature; but no olfactory disorders. The results of micro-PET/CT and western blotting indicated that the dopaminergic system was impaired in astrocytic GLT-1 knockdown rats. Similarly, tyrosine hydroxylase (TH) positive immune-staining in neurons of astrocytic GLT-1 knockdown rats showed deficit in cell count. In vitro, knockdown of astrocytic GLT-1 via RNA interference led to morphological injury of TH-positive neurons, which may be related to the abnormal calcium signal induced by glutamate accumulation after GLT-1 knockdown. Furthermore, the GLT-1 agonist ceftriaxone showed a protective effect on TH-positive neuron impairment. Conclusion:The present findings may shed new light in the future prevention and treatment of PD based on blocking glutamate excitotoxicity.

Keywords: GLT-1, astrocyte, Parkinson’s disease, glutamate, calcium signaling

DOI: 10.3233/JPD-212640

Journal: Journal of Parkinson's Disease, vol. 12, no. 1, pp. 295-314, 2022