Visual dysfunction in a mouse model of chemotherapy-related neurotoxicity.

Abstract

e24059 Background: Chemotherapy-related neurotoxicity (CRNT) poses challenges to long-term outcomes of cancer survivors. Visual function remains relatively unexplored in CRNT. Preliminary clinical work from our group suggests contrast sensitivity may be impaired in patients receiving chemotherapy. Here, we sought to isolate effects of chemotherapy on visual dysfunction in a mouse model. Methods: 10-week old C57BL/6J mice received either 4, 7, or 10 weekly intraperitoneal injections of chemotherapy (CTX group; n=15) or physiologic saline (SAL group; n=12). CTX mice received cyclophosphamide (50 mg/kg) and doxorubicin (2 mg/kg). Contrast sensitivity was assessed using an optomotor response (OMR) chamber. Psychometric functions were fitted to OMR contrast response functions to derive measures of contrast sensitivity (K), stimulus responsivity (Rmax), and stimulus selectivity (n). Electroretinography (ERG) waveforms, which measure light-evoked retinal neural activity, were recorded under scotopic (rod-driven) conditions and decomposed to isolate photoreceptor (a-wave), bipolar cell (b-wave), and interneuron amacrine cell (oscillatory potentials [OP]) activity. OMR and ERG were measured prior to and following treatment. Dependent- and independent-sample t-tests assessed within- and between-group changes, respectively, in outcome measures. Results: Outcome measures are reported in Table 1. SAL relative to CTX mice showed greater weight gain (p=0.004). OMR revealed increases in Rmax (pCTX=0.002; pSAL=0.11) and K (pCTX=0.80; pSAL=0.06) parameters in SAL but not CTX mice. ERG results revealed significant declines in OP peak frequency in CTX relative to SAL mice (p=0.006). Other OMR and ERG measures showed no within- or between-group differences (p>0.10). Decreases in weight were associated with decreases in Rmax (R2=0.25, p=.008) and OP peak frequency (R2=0.20, p=.02). Conclusions: Our animal model showed chemotherapy-related visual dysfunction. Mice receiving chemotherapy showed relative declines in contrast sensitivity, stimulus responsivity, and oscillatory neural activity, suggestive of disrupted neuronal circuits within the visual pathway. Future studies will focus on understanding neuronal mechanisms of visual pathway dysfunction and translating findings to clinical studies. [Table: see text]