机构：[1]Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China[2]Institute of Radiotherapy & Oncology, Soochow University, Suzhou, China[3]Suzhou Key Laboratory for Radiation Oncology, Suzhou, China[4]Department of Radiotherapy and Oncology, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, China[5]Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou, China
Cognitive deficits, characterized by progressive problems with hippocampus-dependent learning, memory and spatial processing, are the most serious complication of cranial irradiation. However, the underlying mechanisms remain obscure. The p75 neurotrophin receptor (p75(NTR)) is involved in a diverse arrays of cellular responses, including neurite outgrowth, neurogenesis, and negative regulation of spine density, which are associated with various neurological disorders. In this study, male Sprague-Dawley (SD) rats received 10 Gy cranial irradiation. Then, we evaluated the expression of p75NTR in the hippocampus after cranial irradiation and explored its potential role in radiation-induced synaptic dysfunction and memory deficits. We found that the expression of p75(NTR) was significantly increased in the irradiated rat hippocampus. Knockdown of p75(NTR) by intrahippocampal infusion of AAV8-shp75 ameliorated dendritic spine abnormalities, and restored synapse-related protein levels, thus preventing memory deficits, likely through normalization the phosphor-AKT activity. Moreover, viral-mediated overexpression of p75(NTR) in the normal hippocampus reproduced learning and memory deficits. Overall, this study demonstrates that p75(NTR) is an important mediator of irradiation-induced cognitive deficits by regulating dendritic development and synapse structure.
基金：
This work was supported by the National Natural Science Foundation of China, Grant nos. 81372411, 81172128 and 81402517; Jiangsu Provincial Special Program of Clinical Medical Science No. BL2014040; Suzhou Science and Technology Project No. SYS201651; Graduate Scientific Research and Innovation Project of Soochow University No. KYLX15_1229 and KYLX14_1267. Jiangsu Provincial Medical Youth Talent QNRC2016234.
第一作者机构：[1]Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China[2]Institute of Radiotherapy & Oncology, Soochow University, Suzhou, China[3]Suzhou Key Laboratory for Radiation Oncology, Suzhou, China
共同第一作者：
通讯作者：
通讯机构：[1]Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China[2]Institute of Radiotherapy & Oncology, Soochow University, Suzhou, China[3]Suzhou Key Laboratory for Radiation Oncology, Suzhou, China
医学