Cochlear Neurotrophin‐3 overexpression at mid‐life prevents age‐related inner hair cell synaptopathy and slows age‐related hearing loss

Abstract

Age-related hearing loss (ARHL) is the most prevalent sensory deficit in the elderly.This progressive pathology often has psychological and medical comorbidities, including social isolation, depression, and cognitive decline. Despite ARHL's enormous societal and economic impact, no therapies to prevent or slow its progression exist. Loss of synapses between inner hair cells (IHCs) and spiral ganglion neurons (SGNs), a.k.a. IHC synaptopathy, is an early event in cochlear aging, preceding neuronal and hair cell loss. To determine if age-related IHC synaptopathy can be prevented, and if this impacts the time-course of ARHL, we tested the effects of cochlear overexpression of neurotrophin-3 (Ntf3) starting at middle age. We chose Ntf3 because this neurotrophin regulates the formation of IHC-SGN synapses in the neonatal period. We now show that triggering Ntf3 overexpression by IHC supporting cells starting in middle age rapidly increases the amplitude of sound-evoked neural potentials compared with age-matched controls, indicating that Ntf3 produces a positive effect on cochlear function when the pathology is minimal. Furthermore, near the end of their lifespan, Ntf3-overexpressing mice have milder ARHL, with larger sound-evoked potentials along the ascending auditory pathway and reduced IHC synaptopathy compared with age-matched controls. Our results also provide evidence that an age-related decrease in cochlear Ntf3 expression contributes to ARHL and that Ntf3 supplementation could serve as a therapeutic for this prevalent disorder. Furthermore, these findings suggest that factors that regulate synaptogenesis during development could prevent age-related synaptopathy in the brain, a process involved in several central nervous system degenerative disorders.

Eurycomanone from <i>Eurycoma longifolia</i> Jack upregulates neurotrophin-3 gene expression in ‍retinal Müller cells <i>in vitro</i>

“…( 29 ) To overcome these limitations, the potency of adeno-associated virus (AAV) gene therapy to increase intracellular NT3 levels has been explored for several diseases, including sarcopenia, ( 30 ) Charcot-Marie-Tooth disease, ( 31 ) and cochlear synaptopathy. ( 32 , 33 ) Furthermore, intravitreal injection of AAV-encoding BDNF or ciliary neurotrophic factor effectively promotes the viability and regeneration of injured adult retinal ganglion cells in rats. ( 34 ) While intraocular injections represent an important technique for treating many retinal conditions that can lead to vision loss, they are not less invasive.…”

From hidden hearing loss to supranormal auditory processing by neurotrophin 3-mediated modulation of inner hair cell synapse density

“…We previously demonstrated that increasing cochlear Ntf3 availability after noise exposure induces IHC synapse regeneration and recovery of ABR peak I amplitudes [ 19 , 80 , 81 ]. More recently, we showed that increasing cochlear Ntf3 expression levels in the middle-aged mouse acutely increases ABR peak I amplitudes and slows the progression of age-related synaptopathy, preserving the IHC synapse density of middle age until the end of the lifespan [ 82 ]. The results from the current study suggest that Ntf3-based therapies could not only promote IHC synapse health and numbers, but also improve auditory processing after noise trauma or in aging.…”

Regeneration of Hair Cells from Endogenous Otic Progenitors in the Adult Mammalian Cochlea: Understanding Its Origins and Future Directions

“…Protection of SGNs by neurotrophins after cochlear damage has been widely studied (for review, see [56]). The four types of neurotrophin nerve growth factor (NGF), BDNF, NT-3, and NT-4/5 participate during cochlear development, and exogenous treatment has been shown to ameliorate SGN loss and improve the number of ribbon synapses after cochlear damage in animal studies [176][177][178][179][180][181]. Other novel therapies involve drugs targeting different molecules in the cochlea, such as the repulsive guidance molecule (RGMa) with antibodies or using Trk receptor agonists; these strategies have been shown to promote neuronal survival, restore synapse after damage and even restore hearing to control levels in adult mice [182][183][184].…”