Synaptic uncoupling in the mouse cochlea induced by noise or cisplatin and its clinical relevance

Abstract: The cochlea has an autonomous circadian clock that controls auditory function and increases vulnerability to noise trauma during the active phase. The mechanisms regulating the circadian control of the auditory system are poorly understood. Furthermore, it remains unclear whether the circadian vulnerability to noise also applies to other auditory insults such as cisplatin, an anticancer drug with strong ototoxic side-effects. Here, we investigated the interplay between glucocorticoids or glutamate homeostasis and noise- or cisplatin-induced hearing loss in the context of circadian influences. Circulating glucocorticoids are important synchronizers of clock rhythms and play a role in noise vulnerability. Our results showed that the removal of adrenal glands, and the subsequent suppression of circadian glucocorticoid rhythms, rescued the increased sensitivity to noise exposure at nighttime. The greater vulnerability to night-noise trauma was associated with a glucocorticoid-dependent regulation of inflammatory genes in the cochlea. Dexamethasone, a synthetic glucocorticoid receptor agonist, protected from noise damage when administered at daytime, coinciding with endogenous circulating glucocorticoid levels being low, but was not equally effective at nighttime, highlighting the relevance of considering the time of the day for assessing the effectiveness of a drug. In parallel, we hypothesized that disruption of the auditory glutamatergic synapse could exacerbate the circadian impact of auditory insults. In a first step, we characterized the synapse status in mice lacking the glutamate transporter GLAST and found that GLAST deficient mice have a pre-existing auditory synaptopathy, which led to an increased sound-evoked activity in the inferior colliculus, something that was not seen in wild-type mice. GLAST deficient mice also showed greater vulnerability to cisplatin-induced ototoxicity at nighttime, with a near complete loss of synaptic coupling to the inner hair cell. This effect could be due to the direct impact of cisplatin on the clock machinery since the administration of cisplatin on ex-vivo cochleae at nighttime altered the rhythms of the clock protein Period2 in a dose dependent manner. A meta-analysis identified five genes that are associated with cisplatin-mediated ototoxicity in cancer patients. Four of these were found circadian in the mouse cochlea, also suggesting their involvement in the circadian vulnerability to cisplatin. Overall, considering chronopharmacological approaches to cisplatin treatment could diminish the adverse side-effects on the auditory system and improve the life quality of cancer survivors.