Cisplatin neurotoxicity targets specific subpopulations and K+ channels in tyrosine-hydroxylase positive dorsal root ganglia neurons

Among the features of cisplatin chemotherapy-induced peripheral neuropathy are chronic pain and innocuous mechanical hypersensitivity. The complete etiology of the latter remains unknown. Here, we show that cisplatin targets a heterogeneous population of tyrosine hydroxylase-positive (TH+) primary afferent dorsal root ganglion neurons (DRGNs) within the primary afferent dorsal root ganglia in mice, determined using single-cell transcriptome and electrophysiological analyses. TH+ DRGNs regulate innocuous mechanical sensation through C-low threshold mechanoreceptors. A differential assessment of wild-type and vitamin E deficient TH+ DRGNs revealed heterogeneity and specific functional phenotypes. The TH+ DRGNs comprise; fast-adapting eliciting one action potential (AP; 1-AP), moderately-adapting (≥ 2-APs), in responses to square-pulse current injection, and spontaneously firing (SF). Cisplatin increased the input resistance and AP frequency but reduced the temporal coding feature of 1-AP and ≥ 2-APs neurons. By contrast, cisplatin has no measurable effect on the SF neurons. Vitamin E reduced the cisplatin-mediated increased excitability, but did not improve the TH+ neuron temporal coding properties. Cisplatin mediates its effect by targeting outward K+ current, likely carried by through K2P18.1 (Kcnk18) , discovered through the differential transcriptome studies and heterologous expression. Studies show a potential new cellular target for chemotherapy-induced peripheral neuropathy and implicate the possible neuroprotective effects of vitamin E in cisplatin chemotherapy. ### Competing Interest Statement The authors have declared no competing interest. * AP : action potential AVED : ataxia with vitamin E deficiency CIPN : cisplatin-induced peripheral neuropathy C-LTMRs : C-low threshold mechanoreceptors DRGN : dorsal root ganglia neurons IACUC : institutional animal care and use committee scRNA-seq : single-cell RNA-sequencing TH : tyrosine hydroxylase Ttpa : tocopherol transfer protein (alpha) SF : spontaneously firing smFISH : single molecule fluorescence in-situ hybridization UCD : University of California Davis UCR : University of Reno