A mouse model with postnatal endolymphatic hydrops and hearing loss.

Endolymphatic hydrops (ELH), hearing loss and neuronal degeneration occur together in a variety of clinically significant disorders, including Meniere's disease (MD). However, the sequence of these pathological changes and their relationship to each other are not well understood. In this regard, an animal model that spontaneously develops these features postnatally would be useful for research purposes. A search for such a model led us to the Phex Hyp-Duk mouse, a mutant allele of the Phex gene causing X-linked hypophosphatemic rickets. The hemizygous male (Phex Hyp-Duk/Y) was previously reported to exhibit various abnormalities during adulthood, including thickening of bone, ELH and hearing loss. The reported inner-ear phenotype was suggestive of progressive pathology and spontaneous development of ELH postnatally, but not conclusive. The main focuses of this report are to further characterize the inner ear phenotype in Phex Hyp-Duk/Y mice and to test the hypotheses that (a) the Phex Hyp-Duk/Y mouse develops ELH and hearing loss postnatally, and (b) the development of ELH in the Phex Hyp-Duk/Y mouse is associated with obstruction of the endolymphatic duct (ED) due to thickening of the surrounding bone. Auditory brainstem response (ABR) recordings at various times points and histological analysis of representative temporal bones reveal that Phex Hyp-Duk/Y mice typically develop adult onset, asymmetric, progressive hearing loss closely followed by the onset of ELH. ABR and histological data show that functional degeneration precedes structural degeneration. The major degenerative correlate of hearing loss and ELH in the mutants is the primary loss of spiral ganglion cells. Further, Phex Hyp-Duk/Y mice develop ELH without evidence of ED obstruction, supporting the idea that ELH can be induced by a mechanism other than the blockade of longitudinal flow of endolymphatic fluid, and occlusion of ED is not a prerequisite for the development of ELH in patients.

Molecular changes associated with the endolymphatic hydrops model.

HYPOTHESIS: Hearing loss and cochlear degeneration in the guinea pig model of endolymphatic hydrops (ELH) results, in part, from toxic levels of excitatory amino acids (EAAs) such as glutamate, which in turn leads to changes in the expression of genes linked to intracellular glutamate homeostasis and apoptosis, leading to neuronal cell death. BACKGROUND: EAAs have been shown to play a role in normal auditory signal transmission in mammalian cochlea, but have also been implicated in neurotoxicity when levels are elevated. Changes in the expression of specific genes involved in the glutamatergic and apoptotic pathway would serve as evidence for excitotoxicity linked to elevated levels of glutamate. METHODS: Guinea pigs underwent surgical obliteration of the endolymphatic duct, and then a timed harvest of the treated (right) and control (left) cochlea and subsequent quantification of gene expression via real-time quantitative polymerase chain reaction. RESULTS: Quantitative polymerase chain reaction data show significant upregulation of glutamate aspartate transporter and neuronal nitric oxide synthase mRNA levels 3 weeks postsurgery and Caspase 3 mRNA levels 1 week postsurgery. No significant changes were detected in glutamine synthetase expression levels. CONCLUSION: Upregulation of genes involved in glutamate homeostasis and the apoptotic pathway in animals treated with endolymphatic duct obstruction (usually associated with secondary ELH) support the hypothesis that EAAs may play a role in the pathophysiology of ELH-related cochlear injury. Inhibitors to these pathways can be useful for the study of new avenues to delay or prevent ELH-related hearing loss.