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. 2013 Oct;110(8):1848-59.
doi: 10.1152/jn.00151.2013. Epub 2013 Jul 31.

Glycinergic Synaptic Transmission in the Cochlear Nucleus of Mice With Normal Hearing and Age-Related Hearing Loss

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Free PMC article

Glycinergic Synaptic Transmission in the Cochlear Nucleus of Mice With Normal Hearing and Age-Related Hearing Loss

Ruili Xie et al. J Neurophysiol. .
Free PMC article

Abstract

The principal inhibitory neurotransmitter in the mammalian cochlear nucleus (CN) is glycine. During age-related hearing loss (AHL), glycinergic inhibition becomes weaker in CN. However, it is unclear what aspects of glycinergic transmission are responsible for weaker inhibition with AHL. We examined glycinergic transmission onto bushy cells of the anteroventral CN in normal-hearing CBA/CaJ mice and in DBA/2J mice, a strain that exhibits an early onset AHL. Glycinergic synaptic transmission was examined in brain slices of mice at 10-15 postnatal days old, 20-35 days old, and at 6-7 mo old. Spontaneous inhibitory postsynaptic current (sIPSC) event frequency and amplitude were the same among all three ages in both strains of mice. However, the amplitudes of IPSCs evoked (eIPSC) from stimulating the dorsal CN were smaller, and the failure rate was higher, with increasing age due to decreased quantal content in both mouse strains, independent of hearing status. The coefficient of variation of the eIPSC amplitude also increased with age. The decay time constant (τ) of sIPSCs and eIPSCs were constant in CBA/CaJ mice at all ages, but were significantly slower in DBA/2J mice at postnatal days 20-35, following the onset of AHL, and not at earlier or later ages. Our results suggest that glycinergic inhibition at the synapses onto bushy cells becomes weaker and less reliable with age through changes in release. However, the hearing loss in DBA/2J mice is accompanied by a transiently enhanced inhibition, which could disrupt the balance of excitation and inhibition.

Keywords: bushy cells; glycinergic inhibition; presbycusis; quantal content; ventral cochlear nucleus.

Figures

Fig. 1.
Fig. 1.
Auditory brain stem response (ABR) thresholds in CBA/CaJ and DBA/2J mice at 3 ages. While CBA/CaJ mice have little threshold shift up to an age of 7 mo, DBA/2J mice show a hearing loss that starts at high frequencies and progresses to lower frequencies as the mice age. Thresholds >70 dB sound pressure level (SPL) are indicated as 70 dB SPL due to limitations of the speaker used to deliver the test sounds. The number of mice tested in each group is indicated in parentheses in the legend. P16 and P21, postnatal days 16 and 21, respectively; 7m and 2m, 7 and 2 mo of age, respectively.
Fig. 2.
Fig. 2.
Spontaneous inhibitory postsynaptic currents (sIPSCs) in bushy cells from CBA/CaJ and DBA/2J mice. A: example traces of sIPSCs in bushy cells from CBA/CaJ and DBA/2J mice at different age groups. The color code indicates strain and age (CBA: black P10–15, green P20–35, and blue 6–7 mo; DBA: gray P10–15, red P20–35, and brown 6–7 mo), and also applies to panels B–G, as well as to Figs. 3, 4, and 6. B: kinetics of the averaged sIPSCs from cells in A. Traces were normalized to the peak to allow comparison of the time course. Note the slow decay of sIPSCs in P20–35 DBA/2J mice compared with other ages and to CBA/CaJ mice. CG: summaries of weighted decay time constant (τ) for averaged sIPSCs (C), sIPSC half-width (D), sIPSC 20–80% rise time (E), sIPSC frequency (F), and sIPSC average amplitude (G) for all bushy cells in each group. Values and number of cells are also summarized in Table 1. Open bars: CBA/CaJ mice; filled bars: DBA/2J mice. ***Bonferroni-corrected posttest after two-way ANOVA: P < 0.001.
Fig. 3.
Fig. 3.
Evoked spontaneous inhibitory postsynaptic currents (eIPSCs) in bushy cells from CBA/CaJ and DBA/2J mice. A: example traces of eIPSCs in bushy cells from CBA/CaJ and DBA/2J mice at different age groups. The color coding is the same as in Fig. 2 and applies to panels BD. Arrows: stimulus onset. The stimulus artifact is removed for clarity. Thin gray lines: individual eIPSCs; thick color lines: average eIPSCs. B: kinetics of the averaged eIPSCs from cells in A. Traces were normalized to the peak to allow comparison of the time course. Note the slower decay of eIPSCs in P20–35 DBA/2J mice compared with other ages and to CBA/CaJ mice. C: summary of weighted decay τ for averaged eIPSCs. ***Bonferroni-corrected posttest after two-way ANOVA: P < 0.001. D: average eIPSC amplitude decreases with age in both CBA/CaJ and DBA/2J mice. *Dunn's posttest after Kruskal-Wallis test: P < 0.05; **Tukey posttest after one-way ANOVA: P < 0.01. See Table 1 and text for values and detailed statistics.
Fig. 4.
Fig. 4.
Quantal content decreases and release failure rate increases with age at the glycinergic synapse onto bushy cells. A: comparison of the estimated quantal content using the ratio of average eIPSC to sIPSC amplitudes and using the method of failures (see materials and methods), for individual cells. Dashed line: prediction of equal quantal content for the two methods. Cells with no failures in eIPSCs are not plotted in A. B: the average quantal content of eIPSC is reduced with age in both CBA/CaJ and DBA/2J mice. Quantal content was estimated using the amplitude method. See Table 1 for details in statistics. *Dunn's posttest after Kruskal-Wallis test: P < 0.05; **Tukey posttest after one-way ANOVA: P < 0.01. C: the paired-pulse ratio (PPR) at a 50-ms interval did not change with age in either mouse strain, suggesting that release probability does not change with age. Inset: example trace of PPR at 50-ms interval. Arrow: stimulus onset; stimulus artifacts are removed for clarity. D: coefficient of variation (CV) of sIPSC peak amplitude does not change with age in both CBA/CaJ and DBA/2J mice. E: CV of eIPSC peak amplitude increases with age in both CBA/CaJ and DBA/2J mice. **Tukey posttest after one-way ANOVA: P < 0.01. F: eIPSC failure rate increases with age in both CBA/CaJ and DBA/2J mice. Inset: example evoked IPSCs in a bushy cell from a 7-mo-old DBA/2J mouse. Notice that the responses are all or none, and the trials with failures of release (gray) can be easily separated from trials with successful release (blue). **Dunn's posttest after Kruskal-Wallis test: P < 0.01. See Table 1 for detailed statistics.
Fig. 5.
Fig. 5.
eIPSC kinetics become slower during repeated stimulation in both CBA/CaJ and DBA/2J mice. A: example traces of single eIPSCs (top) and last three eIPSCs of 50 pulse trains at 100 Hz (bottom) obtained from a bushy cell of a P22 DBA/2J mouse. Inset in the bottom panel shows an averaged trace for the 100-Hz train. Ticks on top mark the time of the 50 stimuli during the train. Stimulus artifacts are removed. B: comparison of IPSC traces between single eIPSC (thin trace) and last eIPSC of the 100-Hz 50 pulse train (thick trace). Traces are normalized to the peak of the IPSCs. C: example IPSCs in a bushy cell from a CBA mouse at P10. In the majority of the trials, excitatory postsynaptic currents could not be elicited during the second half of the stimulus train. Black trace: the average IPSC of all 12 trials. D: ratio of eIPSC decay τ (last eIPSC/single eIPSC) for 100-Hz trains. Ratios were computed for individual cells.
Fig. 6.
Fig. 6.
Short-term synaptic dynamics during repeated stimulation differ between CBA/CaJ and DBA/2J mice. A: eIPSCs during a 100-Hz stimulus train (50 pulses) from example bushy cells of CBA/CaJ and DBA/2J mice at two different ages. Ticks above the traces mark stimulus timing, and the dashed line is the resting current. Stimulus artifacts are removed for clarity. B: normalized eIPSC size relative to the first eIPSC during the 100-Hz train (as in A) from all bushy cells. CBA/CaJ mice show slight facilitation during the train, while DBA/2J mice show initial facilitation followed by depression. C: summary of the average steady-state eIPSCs, shown as the normalized mean of the last 40 eIPSCs during the train relative to the first eIPSC, from all bushy cells in each group. *Bonferroni-corrected posttest after two-way ANOVA: P < 0.05. D: summary of steady-state charges, calculated as the cumulative charge from the last 40 eIPSCs of the train, from all bushy cells. **Bonferroni-corrected posttest following two-way ANOVA: P < 0.01.

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