Roles of neurotrophins in the long-term maintenance of inner ear structure and function

GÓMEZ-CASATI ME

Aruba

Congreso; Pew annual meeting; 2008

In spite of the prevalence of progressive hearing and balance disorders, the cellular and molecular mechanisms that contribute to the long-term structural and functional integrity of the cochlea and vestibular organs remain poorly understood. Studies from Dr. Corfas’ laboratory have implicated erbB receptor signaling in supporting cells of inner ear sensory epithelia in the maintenance of postnatal auditory and vestibular function. When erbB signaling is disrupted in supporting cells by postnatal expression of a dominant-negative erbB receptor, mice loss hearing and vestibular function. Interestingly, this dysfunction is preceded by a reduction in the expression of specific neurotrophic factors, NT3 in the cochlea and BDNF in the vestibular organs, suggesting they play key roles in the observed phenotypes. This is quite remarkable because these neurotrophins have previously been shown to be essential for normal inner ear development, but there was no evidence that they are also required in the adult. These results, together with those obtained by analyzing the correlation between the presence of supporting cells and long-term neuronal survival after hair cell loss, indicate that supporting cells are key regulators of long-term neuronal survival in the inner ear, a departure from the widely accepted view that hair cells are the main source of trophic support for sensory neurons. Based on these observations, I hypothesize that sensory neurons in the inner ear use neuregulin to activate erbB receptors in supporting cells, inducing them to secrete neurotrophins. These neurotrophins then act on the neurons maintaining their synaptic contacts with hair cells, inducing their survival and preserving their function. My aim is to directly test the roles of NT3 and BDNF in the long-term maintenance of cochlear and vestibular structure and function in the postnatal and adult inner ear. To this end I will generate conditional genetically altered mice with either decreased or increased neurotrophin expression in supporting cells. As a counterpart to the manipulation of supporting cells, I will perform similar experiments using conditional gene excision or activation in hair cells to define the contribution of hair cell-derived neurotrophins to maintenance of inner ear function. The roles of the neurotrophins will be defined by phenotypic analysis using molecular, functional and histological techniques. These experiments will provide important insight into mechanisms underlying the pathogenesis of sensorineural hearing and balance disorders.