Alessandra Cervantes
Research Mentor: Gabriel Corfas
Mentor Department: Kesge Hearing Research Institute, Medicine
Author(s): Alessandra Cervantes, Alessandra Cervantes, Luis Cassinotti, Naomi Richelew, John Hakenjos, Natalie Make, Haroon Lughmani, M. Charles Liberman, Gabriel Corfas
Session: Session 1 (9:00 AM – 9:50 AM)
Presentation Type: Poster 94
Abstract
Trk tyrosine kinase receptors and their ligands, the neurotrophins BDNF and Ntf3, are essential for the development and survival of inner ear neurons during embryogenesis. However, their function in adulthood remains unclear. We previously demonstrated that Ntf3 regulates ribbon synapse density in the neonate, its overexpression induces synapse regeneration after acoustic trauma in the young and reduces age-related inner hair cell (IHC) synaptopathy starting at middle age, thus reducing age-related hearing impairment. To further investigate Trk signaling in the adult inner ear, we examined effects of chronic Trk receptor inhibition on auditory function using Larotrectinib/LOXO-101, a Trk inhibitor used for cancer treatment. Adult (9-week-old) CBA/CaJ mice were treated with Larotrectinib (100mg/kg/day, gavage) or vehicle (10% DMSO 5% glucose). To test if Trk inhibition alters normal auditory function, mice were treated daily, and ABRs and DPOAEs were measured at baseline and at days 1, 7, 14 and 21 of treatment. Chronic Trk inhibition caused a progressive reduction in ABR P1 amplitudes, initially at high frequencies (32kHz) and later at mid frequencies (>11kHz) but did not alter hair cell or ribbon synapses numbers (at 22.6kHz), suggesting that the reduced amplitudes reflect reduced synaptic function. Furthermore, the ABR P1 amplitudes recovered after treatment cessation, demonstrating that IHC synapse function requires constant Trk signaling. Trk signaling is required for normal adult auditory function, and its inhibition does not alter IHC or IHC ribbon density but may attenuate their function. The results also suggest that cancer patients receiving Trk inhibitors may be vulnerable to develop hearing problems.
