P. Avan

Hypervulnerability to Sound Exposure through Impaired Adaptive Proliferation of Peroxisomes

A deficiency in pejvakin, a protein of unknown function, causes a strikingly heterogeneous form of human deafness. Pejvakin-deficient (Pjvk(-/-)) mice also exhibit variable auditory phenotypes. Correlation between their hearing thresholds and the number of pups per cage suggest a possible harmful effect of pup vocalizations. Direct sound or electrical stimulation show that the cochlear sensory hair cells and auditory pathway neurons of Pjvk(-/-) mice and patients are exceptionally vulnerable to sound. Subcellular analysis revealed that pejvakin is associated with peroxisomes and required for their oxidative-stress-induced proliferation. Pjvk(-/-) cochleas display features of marked oxidative stress and impaired antioxidant defenses, and peroxisomes in Pjvk(-/-) hair cells show structural abnormalities after the onset of hearing. Noise exposure rapidly upregulates Pjvk cochlear transcription in wild-type mice and triggers peroxisome proliferation in hair cells and primary auditory neurons. Our results reveal that the antioxidant activity of peroxisomes protects the auditory system against noise-induced damage.

Hearing Is Normal without Connexin30

Gjb2 and Gjb6, two contiguous genes respectively encoding the gap junction protein connexin26 (Cx26) and connexin 30 (Cx30) display overlapping expression in the inner ear. Both have been linked to the most frequent monogenic hearing impairment, the recessive isolated deafness DFNB1. Although there is robust evidence for the direct involvement of Cx26 in cochlear functions, the contribution of Cx30 is unclear since deletion of Cx30 strongly downregulates Cx26 both in human and in mouse. Thus, it is imperative that any role of Cx30 in audition be clearly evaluated. Here, we developed a new Cx30 knock-out mouse model (Cx30Δ/Δ) in which half of Cx26 expression was preserved. Our results show that Cx30 and Cx26 coordinated expression is dependent on the spacing of their surrounding chromosomic region, and that Cx30Δ/Δ mutants display normal hearing. Thus, in deaf patients with GJB6 deletion as well as in the previous Cx30 knock-out mouse model, defective Cx26 expression is the likely cause of deafness, and in contrast to current opinion, Cx30 is dispensable for cochlear functions.

The CD2 isoform of protocadherin‐15 is an essential component of the tip‐link complex in mature auditory hair cells

Protocadherin‐15 (Pcdh15) is a component of the tip‐links, the extracellular filaments that gate hair cell mechano‐electrical transduction channels in the inner ear. There are three Pcdh15 splice isoforms (CD1, CD2 and CD3), which only differ by their cytoplasmic domains; they are thought to function redundantly in mechano‐electrical transduction during hair‐bundle development, but whether any of these isoforms composes the tip‐link in mature hair cells remains unknown. By immunolabelling and both morphological and electrophysiological analyses of post‐natal hair cell‐specific conditional knockout mice (Pcdh15ex38‐fl/ex38‐fl Myo15‐cre+/−) that lose only this isoform after normal hair‐bundle development, we show that Pcdh15‐CD2 is an essential component of tip‐links in mature auditory hair cells. The finding, in the homozygous or compound heterozygous state, of a PCDH15 frameshift mutation (p.P1515Tfs*4) that affects only Pcdh15‐CD2, in profoundly deaf children from two unrelated families, extends this conclusion to humans. These results provide key information for identification of new components of the mature auditory mechano‐electrical transduction machinery. This will also serve as a basis for the development of gene therapy for deafness caused by PCDH15 defects.

Patient satisfaction and functional results with the bone-anchored hearing aid (BAHA)

OBJECTIVESnTo assess patient satisfaction with bone-anchored hearing aids (BAHA) and the role of preoperative audiometric testing.nnnPATIENTS AND METHODSnA telephone satisfaction survey was conducted on all patients implanted between June 1, 2005 and February 1, 2008. Patients with unilateral total deafness underwent preoperative audiometric tests in quiet and in noise and stereoaudiometry with and without BAHA. Patients with a conductive hearing loss underwent preoperative audiometric tests in quiet and in noise and real-life testing at home using a headband. A standardized satisfaction questionnaire derived from the Entific BAHA questionnaire was used.nnnRESULTSnTwenty-two out of 26 patients responded to the questionnaire. Ten patients were implanted for conductive hearing loss (CHL) and 12 for unilateral total deafness (UTD). Mean follow-up was 19 months in the UTD group and 21 months in the CHL group. Sixty-seven percent of UTD and 80% of CHL patients reported improved quality of life. The BAHA was worn for more than 4hours per day by 83% of UTD and 100% of CHL patients, and at least 5 days per week by 67% of UTD and 80% of CHL patients.nnnCONCLUSIONnBAHAs provided real benefit in all situations for CHL patients. In UTD, its benefit basically related to noisy environments. In UTD, satisfaction on preoperative stereoaudiometric testing in noise with and without BAHA was predictive of postimplantation satisfaction. In response to the question Would you do it again?, 81% of patients answered Yes.

Mice with a deletion of the major central myelin protein exhibit hypersensitivity to noxious thermal stimuli: involvement of central sensitization

Null mutations in the gene encoding the major myelin protein of the central nervous system, proteolipid protein 1 (PLP1), cause an X-linked form of spastic paraplegia (SPG2) associated with axonal degeneration. While motor symptoms are the best known manifestations of this condition, its somatosensory disturbances have been described but poorly characterized. We carried out a longitudinal study in an animal model of SPG2 - mice carrying a deletion of the Plp1 gene (Plp-null mice). Plp-null mice exhibited severe early-onset thermal hyperalgesia, in the absence of thermal allodynia. We first performed an electrophysiological testing which showed an early decrease in peripheral and spinal conduction velocities in Plp null mice. Such as the abnormal sensitive behaviors, this slowing of nerve conduction was observed before the development of myelin abnormalities at the spinal level, from 3months of age, and without major morphological defects in the sciatic nerve. To understand the link between a decrease in nerve velocity and an increased response to thermal stimuli before the appearance of myelin abnormalities, we focused our attention on the dorsal horn of the spinal cord, the site of integration of somatosensory information. Immunohistochemical studies revealed an early-onset activation of astrocytes and microglia that worsened with age, associated later in age with perturbation of the expression of the sensory neuropeptides calcitonin-gene-related peptide and galanin. Taken together, these results represent complementary data supporting the hypothesis that Plp-null mice suffer from ganglionopathy associated with late onset central demyelination but with few peripheral nerve alterations, induced by the glial-cell-mediated sensitization of the spinal cord. The mechanism suggested here could underlie pain experiments in other leukodystrophies as well as in other non-genetic demyelinating diseases such as multiple sclerosis.

Osteoma of the internal auditory canal.

OBJECTIVEnOsteoma occurs almost exclusively in the head and neck region, only rarely developing into the internal auditory canal. We report an incidental finding of a case in the radiological evaluation of a patient with left hemifacial spasm.nnnPATIENTS AND METHODSnA 79-year-old woman consulted for left hemifacial spasm associated with left anacusis. Symptoms occurred up to 30 years prior to the first radiological investigations. Computed tomographic (CT) and magnetic resonance (MRI) images were taken.nnnRESULTSnMRI demonstrated a left internal auditory canal lesion with spontaneous hypointense signal on T1- and T2-weighted images. CT showed the lesion as a typically dense and opaque osteoma. It measured 0.6 cm in maximum size. No surgery was performed because of the slow-growing features of the lesion. Clinical monitoring was recommended.nnnCONCLUSIONnOsteomas are diagnosed incidentally in asymptomatic patients. Our case was symptomatic and raised the question of surgical management. This article discusses the presentation and management associated with this exceptional osteoma location.

Vasospasm of labyrinthine artery in cerebellopontine angle surgery: evidence brought by distortion-product otoacoustic emissions

In cerebellopontine angle (CPA) surgery, postoperative deafness can be due to alteration of cochlear blood flow that is supplied by the labyrinthine artery (LA). In particular, vasospasm is likely to occur and, if so, can be reversed. This work attempted to track down vascular events occurring during CPA surgery. Twenty consecutive patients with vestibular schwannoma were tested with useful preoperative hearing and presence of otoacoustic emissions (OAEs). Distortion-product otoacoustic emissions (DPOAEs), well-known to react within seconds to cochlear ischemia, were used intraoperatively to indirectly monitor cochlear blood flow. Continuous intraoperative monitoring of DPOAEs revealed three different time patterns associated with distinct auditory outcomes. Pattern P1-acute (nxa0=xa04) happened when the LA was severed: DPOAEs immediately and irreversibly foundered and led to postoperative deafness. Pattern P2-protracted (nxa0=xa07) revealed a progressive deterioration of DPOAEs from the beginning of tumor debulking, likely due to a steady decrease of cochlear blood flow, with postoperative deafness. Pattern P3-unstable (nxa0=xa05) corresponded to large DPOAE oscillations between their normal level and noise floor. It was due to acute LA vasospasm that could be reversed in three cases by topical nimodipin. Last, four patients had uneventful cochlear monitoring. In conclusion, cochlear ischemia can occur in vestibular schwannoma surgery, giving three different patterns among which vasospasm can be reversed if detected early.

Otoferlin acts as a Ca2+ sensor for vesicle fusion and vesicle pool replenishment at auditory hair cell ribbon synapses

Hearing relies on rapid, temporally precise, and sustained neurotransmitter release at the ribbon synapses of sensory cells, the inner hair cells (IHCs). This process requires otoferlin, a six C2-domain, Ca2+-binding transmembrane protein of synaptic vesicles. To decipher the role of otoferlin in the synaptic vesicle cycle, we produced knock-in mice (Otof Ala515,Ala517/Ala515,Ala517) with lower Ca2+-binding affinity of the C2C domain. The IHC ribbon synapse structure, synaptic Ca2+ currents, and otoferlin distribution were unaffected in these mutant mice, but auditory brainstem response wave-I amplitude was reduced. Lower Ca2+ sensitivity and delay of the fast and sustained components of synaptic exocytosis were revealed by membrane capacitance measurement upon modulations of intracellular Ca2+ concentration, by varying Ca2+ influx through voltage-gated Ca2+-channels or Ca2+ uncaging. Otoferlin thus functions as a Ca2+ sensor, setting the rates of primed vesicle fusion with the presynaptic plasma membrane and synaptic vesicle pool replenishment in the IHC active zone.

Acoustic phase shift: Objective evidence for intralabyrinthine pressure disturbance in Menière’s disease provided by otoacoustic emissions

OBJECTIVESnStill today, Menières disease (MD) can be definitively diagnosed only on post-mortem findings of endolymphatic hydrops. Otoacoustic emission (OAE) phase has been shown to be highly sensitive to intracranial pressure. Preliminary analysis of OAEs in MD patients indicated high sensitivity to slight variations in intracranial pressure. The principal objective of the present study was to confirm this specific sensitivity of OAEs in MD.nnnPATIENTS AND METHODSnIn a prospective study of 32 consecutive cases of acute MD seen in consultation or hospital, 20 patients (23 ears) underwent acoustic phase-shift test: i.e., seated vs. supine OAE phase centered around 1kHz, with results compared to controls.nnnRESULTSnThe acoustic phase-shift test was performed in 62.5% of acute patients (58.9% of affected ears). In the control group, the 95% confidence interval for phase shift was between -30° and +45°. Phase shift was significantly elevated, beyond the normal interval, in 18 of the MD patients: range, -80° to +145°. Sensitivity was 90%. Overall, in patients in whom transient evoked OAEs (TEOAEs) were present, positive predictive value was 100% and negative predictive value 92.3%.nnnCONCLUSIONSnThe acoustic phase-shift test proved useful and powerful in demonstrating pressure imbalance in acute Menières disease.

Auditory cortex interneuron development requires cadherins operating hair-cell mechanoelectrical transduction

Significance In early-onset genetic forms of deafness, deficits of the auditory sensory organ are sufficient to account for the hearing impairment. However, the possibility that intrinsic deficits of the auditory cortex (AC) coexist with the peripheral deficits is still unexplored. We show, in rodents and primates, that the cadherin-related proteins cdhr23 and cdhr15 are expressed by many interneuron precursors targeted specifically to the AC. A deficiency of either protein results in the failure of these interneuron precursors to enter the embryonic cortex and in abnormally small numbers of parvalbumin interneurons in the AC only. These findings should lead to an improvement of hearing rehabilitation strategies in patients and open up new genetic approaches for studying AC development and function. Many genetic forms of congenital deafness affect the sound reception antenna of cochlear sensory cells, the hair bundle. The resulting sensory deprivation jeopardizes auditory cortex (AC) maturation. Early prosthetic intervention should revive this process. Nevertheless, this view assumes that no intrinsic AC deficits coexist with the cochlear ones, a possibility as yet unexplored. We show here that many GABAergic interneurons, from their generation in the medial ganglionic eminence up to their settlement in the AC, express two cadherin-related (cdhr) proteins, cdhr23 and cdhr15, that form the hair bundle tip links gating the mechanoelectrical transduction channels. Mutant mice lacking either protein showed a major decrease in the number of parvalbumin interneurons specifically in the AC, and displayed audiogenic reflex seizures. Cdhr15- and Cdhr23-expressing interneuron precursors in Cdhr23−/− and Cdhr15−/− mouse embryos, respectively, failed to enter the embryonic cortex and were scattered throughout the subpallium, consistent with the cell polarity abnormalities we observed in vitro. In the absence of adhesion G protein-coupled receptor V1 (adgrv1), another hair bundle link protein, the entry of Cdhr23- and Cdhr15-expressing interneuron precursors into the embryonic cortex was also impaired. Our results demonstrate that a population of newborn interneurons is endowed with specific cdhr proteins necessary for these cells to reach the developing AC. We suggest that an “early adhesion code” targets populations of interneuron precursors to restricted neocortical regions belonging to the same functional area. These findings open up new perspectives for auditory rehabilitation and cortical therapies in patients.