All Phenotypes Wbp2<tm2a(EUCOMM)Wtsi> MGI Mouse

hearing/vestibular/ear phenotype ( J:229594 )

N

• mice exhibit grossly normal middle and inner ear structure with no overt degeneration of hair cells or spiral ganglion neurons up to 30 weeks of age

• single IHCs show normal mechanoelectrical transducer current and capacitance changes upon depolarisation, suggesting normal neurotransmitter release

abnormal organ of Corti morphology ( J:229594 )

• at P28, TEM analysis of the organ of Corti revealed swelling of afferent terminals below inner and outer hair cells

abnormal cochlear IHC afferent innervation pattern ( J:229594 )

• at P14, afferent terminals below IHCs are slightly swollen in the 24-kHz cochlear region relative to those in wild-type controls

• at P28, severe swelling of afferent terminals is noted under all IHCs, esp. in the 24-kHz region, while some pre-synaptic ribbons do not appear as well aligned to the terminals

• at 4 weeks of age, IHC synapses show reduced expression of GluR2/3 (a marker for AMPA receptor subunits at post-synaptic densities) and poor overlap between pre-synaptic ribbons and post-synaptic densities, suggesting a post-synaptic defect

• TEM analysis showed an array of synaptic phenotypes in the 24-kHz region including: differentially shaped/sized ribbons, orphan post-synaptic densities and orphan ribbons, ribbons with attached synaptic membranes floating in the swollen afferent terminals, as well as close-to-normal looking synapses

• by 8 weeks of age, swollen and retracting terminals are observed, and swelling is more severe in the 24-kHz region compared to the 9-kHz region, consistent with high-frequency hearing loss

• however, the number of pre-synaptic ribbons per IHC is normal in the 8-, 18- and 24-kHz regions at both 4 and 8 weeks of age

abnormal cochlear OHC afferent innervation pattern ( J:229594 )

• at P28, swelling of OHC afferent terminals is observed in the 24-kHz region

abnormal auditory brainstem response waveform shape ( J:229594 )

• at 4 weeks of age, averaged click-evoked ABR waveforms at 50-dB sensation level revealed a normal waveform shape but a reduced ABR amplitude

• ABR wave 1 amplitudes show a significant reduction and a longer latency relative to those in wild-type controls, suggesting reduced auditory nerve activity

increased or absent threshold for auditory brainstem response ( J:229594 )

• although ABR thresholds are normal at P14, mice exhibit increased ABR thresholds at frequencies of 24 kHz or higher by 4 weeks of age

• hearing loss is more evident at 14 and 28 weeks and spreads to lower frequencies by 44 weeks of age

• however, no endocochlear potential deficits are observed

abnormal auditory summating potential ( J:229594 )

• at 4 weeks of age, the summating potential is reduced and grows at a reduced rate as stimulus level increases

• however, latency is similar to that in wild-type controls

abnormal distortion product otoacoustic emission ( J:229594 )

• at 4 weeks of age, mice show increased 2f1-f2 DPOAE thresholds for 24- and 30-kHz f2 tones

• by 21 weeks of age, 2f1-f2 DPOAE thresholds are increased for all test frequencies (6-30 kHz), esp. at 18-30 kHz, indicating OHC dysfunction

sensorineural hearing loss ( J:229594 )

• mice exhibit progressive high-frequency hearing loss from as early as 4 weeks of age

• at 4 weeks of age, hearing loss is associated with reduced expression of Esr1, Esr2 and Pgr, decreased expression of GluR2/3 AMPA subunits, and increased transcription of Shank3 and Dlg4 (encoding Psd-95) in the cochlea as well as increased Psd95 protein levels in IHC synapses, thus linking hearing impairment to hormonal signaling