Auditory circuit organization following gene therapy for congenital deafness

PROJECT SUMMARY This project seeks to understand the critical role of otoferlin in auditory circuit development and how gene therapy can be optimized to restore hearing in patients with congenital deafness caused by otoferlin variants. Otoferlin is a key calcium sensor that facilitates synaptic vesicle fusion and neurotransmitter release at inner hair cell (IHC) synapses, essential for transmitting sound information to the auditory nerve. In individuals that harbor certain otoferlin variants, abnormal function of otoferlin leads to profound hearing loss. Recent clinical trials have successfully restored hearing by delivering functional otoferlin via gene therapy, but there remain unanswered questions about how otoferlin shapes early auditory circuit development and how its restoration influences auditory system organization and plasticity, especially after prolonged deafness. This project aims to examine how otoferlin knockout (Otof KO) mice respond to gene therapy by exploring spontaneous activity patterns, auditory cortex organization, and potential methods to enhance neural plasticity. In this proposal, we will investigate how spontaneous neural activity patterns are disrupted in Otof KO mice, as spontaneous activity is crucial for the development and refinement of sensory circuits. Using widefield imaging techniques, we will examine spontaneous activity in the cochlea, inferior colliculus (IC), and auditory cortex (AC) of Otof KO mice to determine how the absence of otoferlin affects neural signaling before hearing begins. We will also explore how the timing of otoferlin gene therapy influences auditory cortex organization and plasticity. Otof KO mice will receive gene therapy at different developmental stages (P1, P7, and P21), and their cortical responses to sound will be monitored over time. We anticipate that earlier intervention will lead to cortical responses that are indistinguishable from controls, while late intervention will result in loss of tonotopic precision and limited cortical reorganization. To extend these studies, we will investigate whether visual deprivation can enhance plasticity following otoferlin gene therapy. Sensory deprivation, such as placing the treated mice in complete darkness, has been shown to enhance cortical plasticity in the auditory system, suggesting that it could help the cortex adapt more effectively to restored hearing. By examining changes in auditory cortical activity in Otof KO mice following gene therapy and visual deprivation, we hope to identify strategies that could boost plasticity and improve auditory rehabilitation, particularly in adults with congenital deafness who display limited recovery of linguistic abilities when hearing sensation is restored. Together, this research will provide valuable insights into how otoferlin contributes to auditory development, inform optimal timing for gene therapy interventions, and explore novel approaches to enhance plasticity, ultimately improving outcomes for patients undergoing hearing restoration.