The p75 neurotrophin receptor regulates cranial irradiation-induced hippocampus-dependent cognitive dysfunction

// Xin Ding 1, 2, 3, * , Hao-Hao Wu 1, 2, 3, * , Sheng-Jun Ji 1, 4 , Shang Cai 1, 2, 3 , Pei-Wen Dai 1, 2, 3 , Mei-Ling Xu 1, 2, 3 , Jun-Jun Zhang 1, 2, 3 , Qi-Xian Zhang 1, 2, 3 , Ye Tian 1, 2, 3 and Quan-Hong Ma 5 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 * Co-first author Correspondence to: Ye Tian, email: dryetian@126.com Keywords: hippocampus, cognitive dysfunction, neurogenesis, dendritic spine, p75 NTR Received: October 24, 2016      Accepted: February 22, 2017      Published: March 23, 2017 ABSTRACT 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 p75 NTR 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.