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 (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.