The p75 neurotrophin receptor regulates cranial irradiation-induced hippocampus-dependent cognitive dysfunction
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Xin Ding1,2,3,*, Hao-Hao Wu1,2,3,*, Sheng-Jun Ji1,4, Shang Cai1,2,3, Pei-Wen Dai1,2,3, Mei-Ling Xu1,2,3, Jun-Jun Zhang1,2,3, Qi-Xian Zhang1,2,3, Ye Tian1,2,3 and Quan-Hong Ma5
1Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China
2Institute of Radiotherapy & Oncology, Soochow University, Suzhou, China
3Suzhou Key Laboratory for Radiation Oncology, Suzhou, China
4Department of Radiotherapy and Oncology, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, China
5Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou, China
Ye Tian, email: [email protected]
Keywords: hippocampus, cognitive dysfunction, neurogenesis, dendritic spine, p75NTR
Received: October 24, 2016 Accepted: February 22, 2017 Published: March 23, 2017
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 (p75NTR) 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 p75NTR was significantly increased in the irradiated rat hippocampus. Knockdown of p75NTR 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 p75NTR in the normal hippocampus reproduced learning and memory deficits. Overall, this study demonstrates that p75NTR is an important mediator of irradiation-induced cognitive deficits by regulating dendritic development and synapse structure.
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