All Phenotypes Gabra5<tm1Twr> MGI Mouse

• Gabra5-deficient mice show improved memory compared to controls in a Morris water maze 'matching-to-place' test

abnormal cochlea morphology ( J:112951 )

• at 6-10 weeks, homozygotes display minimal cochlear histopathology, with little hair cell loss outside of the extreme cochlear base

• at >24 weeks, homozygotes exhibit basal-turn histopathology

cochlear inner hair cell degeneration ( J:112951 )

• at ~24 weeks, homozygotes display a nearly complete loss of IHCs throughout the basal 15% of the cochlear spiral, i.e. from 40 to 90 kHz according to the mouse cochlear frequency map

abnormal cochlear OHC efferent innervation pattern ( J:112951 )

• however, at 6 weeks, efferent innervation density in the 16 kHz region is still normal, consistent with normal magnitudes of shock-evoked efferent effects observed at this age

• at 24 weeks, degeneration of OHC efferent terminals is observed, as shown by reduced VAT-positive terminals

• no changes in efferent terminal development are noted up to 3 weeks of age

• importantly, no significant loss of afferent terminals is noted at 24 weeks

cochlear outer hair cell degeneration ( J:112951 )

• at ~24 weeks, homozygotes display a nearly complete loss of OHCs throughout the basal 15% of the cochlear spiral, i.e. from 40 to 90 kHz according to the mouse cochlear frequency map

type IV spiral ligament fibrocyte degeneration ( J:112951 )

• at 6-10 weeks, homozygotes show loss of type IV fibrocytes in the spiral ligament of the basal turn

• at >24 weeks, loss of type IV fibrocytes is extended farther apically than at 6 weeks of age

abnormal auditory brainstem response waveform shape ( J:112951 )

• at 6 weeks, amplitudes of ABR suprathreshold responses (wave 1) of homozygotes are reduced by 25-50% relative to wild-type mice, even at the highest test stimulus levels

increased or absent threshold for auditory brainstem response ( J:112951 )

• at 6 weeks, homozygotes display cochlear dysfunction, as shown by significant ABR threshold shifts increasing from <5 to 20-30 dB with increasing tone frequency

• however, at 6 weeks, homozygotes show no significant differences in cochlear vulnerability to acoustic trauma (measured via ABRs and DPOAEs at 12 hrs after a 2-hr exposure to a 8-16 kHz noise band at 89 dB SPL) or in recovery from acoustic trauma at 7 days after overexposure relative to age-matched wild-type control mice

• at 24 weeks, cochlear dysfunction is exacerbated, as mean ABR threshold shifts are shown to peak at 45 dB for test frequencies in the middle of the cochlea (16 kHz)

• at 24 weeks, ABR threshold shifts are significantly larger than the observed DPOAE shifts

• no sexual dimorphism is observed at 24 weeks with respect to ABR threshold shifts

abnormal distortion product otoacoustic emission ( J:112951 )

• at 6 weeks, homozygotes display increasing DPOAE threshold shifts from low to high frequencies

• at 24 weeks, ABR threshold shifts are significantly larger than the observed DPOAE shifts

• however, at 6 weeks, ABR shifts at 16 kHz (middle cochlear region) are similar in magnitude to the observed DPOAE shifts, suggesting that the ongoing degeneration is a type of neuropathy

• in addition, at 6 weeks, OHC efferent function remains unaffected, as assessed by measuring DPOAE suppression caused by efferent-bundle shocks

sensorineural hearing loss ( J:112951 )