title: The p75 neurotrophin receptor regulates cranial irradiation-induced hippocampus-dependent cognitive dysfunction.
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 (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.
authors.affiliation: Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China.|Institute of Radiotherapy & Oncology, Soochow University, Suzhou, China.|Suzhou Key Laboratory for Radiation Oncology, Suzhou, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Ding
authors.affiliation: Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China.|Institute of Radiotherapy & Oncology, Soochow University, Suzhou, China.|Suzhou Key Laboratory for Radiation Oncology, Suzhou, China.
authors.forename: Hao-Hao
authors.initials: HH
authors.lastname: Wu
authors.affiliation: Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China.|Department of Radiotherapy and Oncology, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, China.
authors.forename: Sheng-Jun
authors.initials: SJ
authors.lastname: Ji
authors.affiliation: Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China.|Institute of Radiotherapy & Oncology, Soochow University, Suzhou, China.|Suzhou Key Laboratory for Radiation Oncology, Suzhou, China.
authors.forename: Shang
authors.initials: S
authors.lastname: Cai
authors.affiliation: Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China.|Institute of Radiotherapy & Oncology, Soochow University, Suzhou, China.|Suzhou Key Laboratory for Radiation Oncology, Suzhou, China.
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Dai
authors.affiliation: Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China.|Institute of Radiotherapy & Oncology, Soochow University, Suzhou, China.|Suzhou Key Laboratory for Radiation Oncology, Suzhou, China.
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Xu
authors.affiliation: Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China.|Institute of Radiotherapy & Oncology, Soochow University, Suzhou, China.|Suzhou Key Laboratory for Radiation Oncology, Suzhou, China.
authors.forename: Jun-Jun
authors.initials: JJ
authors.lastname: Zhang
authors.affiliation: Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China.|Institute of Radiotherapy & Oncology, Soochow University, Suzhou, China.|Suzhou Key Laboratory for Radiation Oncology, Suzhou, China.
authors.forename: Qi-Xian
authors.initials: QX
authors.lastname: Zhang
authors.affiliation: Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China.|Institute of Radiotherapy & Oncology, Soochow University, Suzhou, China.|Suzhou Key Laboratory for Radiation Oncology, Suzhou, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou, China.
authors.forename: Quan-Hong
authors.initials: QH
authors.lastname: Ma
mesh_terms: D000818:Animals; D060825:Cognitive Dysfunction / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D016371:Cranial Irradiation / Q000009:adverse effects*; D003712:Dendrites / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D015870:Gene Expression / Q000528:radiation effects; D006624:Hippocampus / Q000378:metabolism / Q000528:radiation effects*; D008297:Male; D008569:Memory Disorders / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D020800:Receptor, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects
chemical_list: D020800:Receptor, Nerve Growth Factor
keywords: cognitive dysfunction; dendritic spine; hippocampus; neurogenesis; p75NTR