Cisplatin is a chemotherapy drug used to treat different solid tumors, including ovarian, bladder, lung, and head and neck cancers. One of its significant side effects is ototoxicity, especially when high doses are required. Cisplatin-induced ototoxicity is associated with increased cochlear cell death resulting from DNA damage, caspase activation, oxidative stress, inflammation, and glutamate excitotoxicity. The regulator of G protein signaling 17 (RGS17), a member of the RGS-RZ subfamily, hastens the hydrolysis of GTP to GDP on the Gα subunit. In the current study, we demonstrate the role of RGS17 in cisplatin-induced cochlear inflammation and ototoxicity. C57BL/6J mice treated with two cycles of cisplatin (3.5 mg/kg) showed a significant elevation in ABR thresholds, along with loss of outer hair cells and inner hair cells synapse. Furthermore, immunohistochemical analysis revealed that cisplatin administration upregulates CXCL1, accompanied by an increase in the number of CD45 and CD68-positive immune cells. On the other hand, RGS17 knockout in hair cells protects against cisplatin-induced elevation of ABR thresholds, outer hair cell loss, cochlear inflammation, and inner hair cell synaptopathy. Moreover, RGS17 knockout downregulates CXCL1 immunolabeling and decreases the number of CD45 and CD68-positive immune cells induced by cisplatin. These results suggest that RGS17 is implicated in cisplatin ototoxicity, potentially by initiating the immune cascade, and indicate RGS17 as a relevant target for treating cisplatin ototoxicity.
Copyright © 2025 Al Aameri, Alanisi, Al Sallami, Alberts, Tischkau, Rybak and Ramkumar.

AMPA-type glutamate receptors (AMPARs) mediate excitatory cochlear transmission. However, unique roles of AMPAR subunits are unresolved. Lack of subunit GluA3 (Gria3 KO ) in male mice reduced cochlear output by 8 postnatal weeks. Here, we studied the role of X-linked Gria3 in cochlear function and synapse anatomy in females. Auditory brainstem responses (ABRs) were similar in 3-week-old female Gria3 WT and Gria3 KO mice raised in quiet. However, after switching to ambient sound, ABR thresholds were elevated and wave-1 amplitudes were diminished at 5-week and older in Gria3 KO . A quiet vivarium precluded this effect. Paired synapses were similar in number, but lone ribbons and ribbonless synapses were more frequent, and swollen afferent terminals were observed only in female Gria3 KO mice in ambient sound. Synaptic GluA4:GluA2 ratios increased relative to Gria3 WT , particularly in ambient sound, suggesting an activity-dependent increase in calcium-permeable AMPARs in Gria3 KO . We propose that lack of GluA3 induces a sex-dependent vulnerability to AMPAR-mediated excitotoxicity.
© 2025 The Author(s).

Our sense of hearing processes sound intensities spanning six orders of magnitude. In the ear, postsynaptic spiral ganglion neurons (SGNs) tile this intensity range with their firing rate codes. Presynaptic inner hair cells (IHCs) vary Ca 2+ -influx among their active zones (AZs) diversifying glutamate release and likely contributing to SGN firing diversity. Here we show that low-voltage activation of IHC-Ca 2+ -influx of mice, modeling the human Ca V 1.3 A749G mutation, increases spontaneous SGN-firing and lowers sound threshold. Altered synaptic morphology in Ca V 1.3 A749G/A749G mice already at ambient sound levels of standard mouse husbandry indicates a risk for noise-induced alterations in Ca V 1.3 A749G patients. We conclude that heterogeneous voltage-dependence of Ca V 1.3 activation among IHC-AZs contributes to the diversity of SGN firing for sound intensity coding and synaptic vulnerability.

Enhancer translocations, due to 3q26 rearrangements, drive out-of-context MECOM expression in an aggressive subtype of acute myeloid leukemia (AML). Direct depletion of MECOM using an endogenous auxin-inducible degron immediately upregulates expression of myeloid differentiation factor CEBPA . MECOM depletion is also accompanied by a severe loss of stem cells and gain of differentiation. MECOM exerts its inhibitory effect by binding to the +42kb CEBPA enhancer, a gene essential for neutrophil development. This is partially dependent on the interaction between MECOM and its co-repressor CTBP2. We demonstrate that CEBPA overexpression can bypass the MECOM-mediated block of differentiation. In addition, AML patients with MECOM overexpression through enhancer hijacking show significantly reduced CEBPA . Our study directly connects two main players of myeloid transformation MECOM and CEBPA , and it provides insight into the mechanism by which MECOM maintains the stem cell state in a unique subtype of AML by inactivating CEBPA .

Deafness is the most common form of sensory impairment in humans and frequently caused by defects in hair cells of the inner ear. Here we demonstrate that in male mice which model recessive non-syndromic deafness (DFNB6), inactivation of Tmie in hair cells disrupts gene expression in the neurons that innervate them. This includes genes regulating axonal pathfinding and synaptogenesis, two processes that are disrupted in the inner ear of the mutant mice. Similar defects are observed in mouse models for deafness caused by mutations in other genes with primary functions in hair cells. Gene therapy targeting hair cells restores hearing and inner ear circuitry in DFNB6 model mice. We conclude that hair cell function is crucial for the establishment of peripheral auditory circuitry. Treatment modalities for deafness thus need to consider restoration of the function of both hair cells and neurons, even when the primary defect occurs in hair cells.
© 2024. The Author(s).