(S047) Radiotherapy vs Chemotherapy Effects on Neuronal Architecture and Spine Density in the Hippocampus

April 30, 2015

Exposure to chemotherapy or RT disrupts the formation and establishment of proper synaptic connections by causing significant alterations in neuronal structure that compromise neurotransmission and cognition.

Nevine Hanna, MD, MPH, Munjal Acharya, PhD, Charles Limoli, PhD; University of California, Irvine

PURPOSE: Studies have shown that cognitive function is compromised by both radiation treatment (RT) and the use of chemotherapy (ie, the “chemobrain” phenomenon). Given that advancements in diagnosis, beam delivery, and drug treatments have extended long-term cancer survivorship, it has become increasingly critical to address the extent and persistence of, and neurobiological mechanisms underlying, cognitive dysfunction associated with cancer treatments. Through immunofluorescence studies in mice, our lab previously established that irradiation elicits significant reductions in neuronal morphology. In the present study, we examine the consistency of the effects of radiation or chronic cyclophosphamide (CYP) treatment, a commonly prescribed chemotherapeutic agent, on animal behavior and neuronal morphology via different staining techniques.

METHODS: Adult athymic nude rats were treated with 9 Gy of x-rays every other day to a total of 27 Gy (biologically effective dose [BED] = 108 Gy) or with CYP (100 mg/kg) once weekly for 4 weeks and compared with sham-irradiated or saline controls, respectively. At 1 month posttreatment, animals were administered hippocampus- and cortex-dependent cognitive tasks, including novel place recognition (NPR) and a temporal order (TO) task. Following cognitive testing, immunohistochemical staining was used to trace immature (doublecortin, DCX+) and mature (Golgi-Cox–impregnated) neurons in the brain for an assessment of neuronal morphology in the CA1 region. Spine density was also counted to delineate the number of long/thin, mushroom, and stubby spines in the same region.

RESULTS: Both irradiated and CYP-treated rats showed significant decrements in learning and memory when assessed on both the NPR and TO tasks. CYP-treated animals were impaired in hippocampus-dependent place recognition memory and cortex-dependent recency memory compared with controls. Quantification of ultrastructural parameters of neurons in the hippocampus using Neurolucida software indicated compromised dendritic morphology in the immature (DCX+) and mature (Golgi-Cox) neurons in the CA1 hippocampal region. Chronic CYP treatment (n = 20) led to significant reductions in the apical dendritic volume (P = .0033), basal total dendritic length (P = .0161), endings (P = .0352), volume (P = .0004), and complexity (including branching and three-dimensional morphology; P = .01) compared with sham. Early analysis (n = 5) is also showing similar significance in the irradiated cohort. With regard to spine density, overall group effects were found for altered numbers of long/thin (P = .0079), mushroom (P = .0048), and stubby (P = .006) spine types in the CA1 region.

CONCLUSIONS: Exposure to chemotherapy or RT disrupts the formation and establishment of proper synaptic connections by causing significant alterations in neuronal structure that compromise neurotransmission and cognition.

Proceedings of the 97th Annual Meeting of the American Radium Society - americanradiumsociety.org