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

Xin Ding,Quan-Hong Ma,Jun-Jun Zhang,Shang Cai,Hao-Hao Wu,Ye Tian,Mei-Ling Xu,Qi-Xian Zhang,Pei-Wen Dai,Sheng-Jun Ji

doi:10.18632/oncotarget.16492

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.

Highlights

Radiotherapy, a commonly applied treatment for brain tumors, may cause serious brain injury, especially damages to the hippocampus, an area important for cognition
The levels of p75 neurotrophin receptor (p75NTR) in the dorsolateral prefrontal cortex (PFC) remained unchanged upon irradiation (Figure 1B). These results suggest a pathological function of p75NTR in radiationinduced cognitive dysfunction
When subcellular localization was analyzed in the dentate gyrus (DG) region, we found that p75NTR immunoreactivity colocalized with NeuN, a specific marker for neurons, suggesting that p75NTR was expressed by hippocampal neurons before and after irradiation (Figure 1D-a and 1D-b)

Summary

Introduction

Radiotherapy, a commonly applied treatment for brain tumors, may cause serious brain injury, especially damages to the hippocampus, an area important for cognition Radiation causes both anatomical and functional changes, which result in impaired hippocampus-dependent learning, memory and spatial processing abilities [1,2,3]. Abnormal neurotrophin levels and aberrant neuroinflammation have been proposed as underlying mechanisms [5], little is known about the precise molecular pathways involved in radiation-induced learning and memory disturbances. Neurotrophins and their receptors play pivotal roles in brain development and in maintaining the physiological functions of the nervous system [6]. The interactions between BDNF and p75NTR are poorly understood

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Conclusion