Abnormal Development of Dendrites in Adult-Born Rat Hippocampal Granule Cells Induced by Cyclophosphamide.

Lin Wu,Fuwu Wang,Fei Gao,Qi Liu,Xiaochen Wang,Ren-Zhi Zhan,Xueying Song,Dandan Guo

doi:10.3389/fncel.2017.00171

Abstract

Although development of cognitive decline in cancer patients who receive chemotherapy is common, the underlying mechanism(s) remains to be identified. As abnormalities in adult hippocampal neurogenesis may serve as substrate for cognitive dysfunction, the present study examines the effect of cyclophosphamide (CPP), a widely prescribed chemotherapeutic agent, on dendritic development of adult-born hippocampal granule cells in the rat. CPP was intraperitoneally injected into male Sprague-Dawley rats once a week for four consecutive weeks. Four weeks and 1 week after the last dose of CPP, Morris water maze test and doublecortin (DCX) immunohistochemistry were carried out to determine the effects of CPP on cognitive function and the rate of hippocampal neurogenesis, respectively. Adult newborn hippocampal granule cells were labeled at the same day as the first dose of CPP and were examined 10 weeks after labeling. Results showed that cognitive decline induced by CPP was associated with both suppressed adult hippocampal neurogenesis and abnormal development of dendrites of newborn granule cells. The abnormalities of dendrites in newborn granule cells after CPP exposure included less dendritic branching, shorter total dendritic length, thinner and torturous dendritic shafts with intermittent appearances of varicosities, and lower spine densities of stubby and thin types along dendritic shafts, but an increased density of mushroom-like spines. Adult-born granule cells in the presence of CPP, a widely used anti-cancer medication, display abnormal dendritic morphologies and fewer dendritic spines which may underlie cognitive dysfunction.

Highlights

In addition to confirming that persistent cognitive decline induced by CPP is associated with a suppression of adult hippocampal neurogenesis, we found that CPP treatment leads to remarkable abnormal development of dendrites in newborn
Animal studies have found that chemotherapeutic agents, including CPP, profoundly slow the rate of adult hippocampal neurogenesis (Mustafa et al, 2008; Seigers et al, 2008, 2009, 2010; Yang et al, 2010; Briones and Woods, 2011; Lyons et al, 2011; Christie et al, 2012; ElBeltagy et al, 2012; Nokia et al, 2012)
Because adult hippocampal neurogenesis is implicated in functions that overlap with those general functions of hippocampus (Clelland et al, 2009; Sahay et al, 2011; Aimone et al, 2014; Christian et al, 2014; Opendak and Gould, 2015), in addition to studying the rate of neurogenesis, studying the intrinsic electrophysiological properties and integration of newborn granule cells under the influence of chemotherapeutic agents is needed

Summary

Introduction

Systemic cancer treatment is associated with cognitive decline that manifests as impairments in learning, memory formation, attention, information processing speed and executive functioning (Anderson-Hanley et al, 2003; Minisini et al, 2004; Vardy and Tannock, 2007; Janelsins et al, 2011; Dietrich et al, 2015; Iyer et al, 2015; Ono et al, 2015; Wefel et al, 2015). Cyclophosphamide and Dendritic Development including biological and neuropsychiatric responses to cancers (Andreotti et al, 2015; Wefel et al, 2015), toxic effects of chemotherapeutic agents (Ahles and Saykin, 2007; Hutchinson et al, 2012; Dietrich et al, 2015) and side effects of adjuvant hormones (Rugo and Ahles, 2003; Castellon et al, 2004) have been proposed for the development of cognitive dysfunction.

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Results

Conclusion