Acoustic trauma slows AMPA receptor-mediated EPSCs in the auditory brainstem, reducing GluA4 subunit expression as a mechanism to rescue binaural function.
Acoustic trauma slows AMPA receptor-mediated EPSCs in the auditory brainstem, reducing GluA4 subunit expression as a mechanism to rescue binaural function.
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DOI：
10.1113/jp271929
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发表时间：
2016-07-01
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通讯作者：
Forsythe ID
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作者：
Pilati N;Linley DM;Selvaskandan H;Uchitel O;Hennig MH;Kopp-Scheinpflug C;Forsythe ID
外侧上级橄榄（LSO）主神经元接受AMPA受体（AMPAR）和NMDA受体（NMDAR）介导的EPSC和甘氨酸能IPSC。EPSC和IPSC在听前动物中具有缓慢的动力学，其在发育成熟期间加速至亚毫秒衰减时间常数。这与通过mRNA水平定量的谷氨酸和甘氨酸受体亚基组成的变化相关。NMDAR-EPSC加速发育，以实现2.5 ms的衰减时间常数。这是报道的最快的NMDAR介导的EPSC。声创伤（AT，响亮的声音）减缓AMPAR-EPSC衰减时间，增加GluA 1和减少GluA 4 mRNA。耳间强度差异的模型表明，AT后EPSC持续时间的增加使耳间水平差异向右移动，并补偿听力损失。AT后两个月，EPSC衰减时间恢复到对照值。LSO中的突触传递在出生后第20天成熟，EPSC和IPSC具有快速动力学。AT改变了AMPAR亚基的表达，并减缓了中枢听觉系统突触处的EPSC时程。破坏性的声音水平（声创伤，AT）减少外周突触，但对中枢听觉通路的影响是什么？使用电压钳和听觉脑干反应表征了出生后第7天（P7）至P96小鼠外侧上级橄榄（LSO）中突触功能和听力的发育成熟。IPSC和EPSC在发育过程中显示出快速加速，因此衰变动力学在成年小鼠中收敛到相似的亚毫秒时间常数（τ，分别为0.87 ± 0.11和0.77 ± 0.08 ms）。这与甘氨酸能和谷氨酸能离子型受体亚基的LSO mRNA水平相关，证实IPSC从Glyα2转换为Glyα1，EPSC的GluA 3和GluA 4亚基表达增加。随着GluN 2C表达的增加，NMDA受体（NMDAR）-EPSC衰减τ从听阈前动物的>40 ms加速到成年动物的2.6 ± 0.4 ms。在P20左右体内诱导AT破坏了LSO中的IPSC和EPSC整合，因此1周后AMPA受体（AMPAR）-EPSC衰减减慢，GluA 1的mRNA增加，而GluA 4减少。相比之下，GlyR IPSC和NMDAR-EPSC衰减时间不变。计算建模证实，需要匹配的IPSC和EPSC动力学来产生成熟的耳间水平差功能，并且更持久的EPSC补偿以维持AT后听觉阈值升高的双耳功能。我们得出结论，LSO兴奋性和抑制性突触驱动成熟到相同的时间过程，AT通过表达具有缓慢动力学的亚基（在2个月内恢复）来改变突触AMPAR，并且响亮的声音可逆地改变大脑中的兴奋性突触，在暴露后数周内改变突触功能。外侧上级橄榄（LSO）主神经元接受AMPA受体（AMPAR）和NMDA受体（NMDAR）介导的EPSC和甘氨酸能IPSC。EPSC和IPSC在听前动物中具有缓慢的动力学，其在发育成熟期间加速至亚毫秒衰减时间常数。这与通过mRNA水平定量的谷氨酸和甘氨酸受体亚基组成的变化相关。NMDAR-EPSC加速发育，以实现2.5 ms的衰减时间常数。这是报道的最快的NMDAR介导的EPSC。声创伤（AT，响亮的声音）减缓AMPAR-EPSC衰减时间，增加GluA 1和减少GluA 4 mRNA。耳间强度差异的模型表明，AT后EPSC持续时间的增加使耳间水平差异向右移动，并补偿听力损失。AT后两个月，EPSC衰减时间恢复到对照值。LSO中的突触传递在出生后第20天成熟，EPSC和IPSC具有快速动力学。AT改变了AMPAR亚基的表达，并减缓了中枢听觉系统突触处的EPSC时程。
Lateral superior olive (LSO) principal neurons receive AMPA receptor (AMPAR) ‐ and NMDA receptor (NMDAR)‐mediated EPSCs and glycinergic IPSCs. Both EPSCs and IPSCs have slow kinetics in prehearing animals, which during developmental maturation accelerate to sub‐millisecond decay time‐constants. This correlates with a change in glutamate and glycine receptor subunit composition quantified via mRNA levels. The NMDAR‐EPSCs accelerate over development to achieve decay time‐constants of 2.5 ms. This is the fastest NMDAR‐mediated EPSC reported. Acoustic trauma (AT, loud sounds) slow AMPAR‐EPSC decay times, increasing GluA1 and decreasing GluA4 mRNA. Modelling of interaural intensity difference suggests that the increased EPSC duration after AT shifts interaural level difference to the right and compensates for hearing loss. Two months after AT the EPSC decay times recovered to control values. Synaptic transmission in the LSO matures by postnatal day 20, with EPSCs and IPSCs having fast kinetics. AT changes the AMPAR subunits expressed and slows the EPSC time‐course at synapses in the central auditory system. Damaging levels of sound (acoustic trauma, AT) diminish peripheral synapses, but what is the impact on the central auditory pathway? Developmental maturation of synaptic function and hearing were characterized in the mouse lateral superior olive (LSO) from postnatal day 7 (P7) to P96 using voltage‐clamp and auditory brainstem responses. IPSCs and EPSCs show rapid acceleration during development, so that decay kinetics converge to similar sub‐millisecond time‐constants (τ, 0.87 ± 0.11 and 0.77 ± 0.08 ms, respectively) in adult mice. This correlated with LSO mRNA levels for glycinergic and glutamatergic ionotropic receptor subunits, confirming a switch from Glyα2 to Glyα1 for IPSCs and increased expression of GluA3 and GluA4 subunits for EPSCs. The NMDA receptor (NMDAR)‐EPSC decay τ accelerated from >40 ms in prehearing animals to 2.6 ± 0.4 ms in adults, as GluN2C expression increased. In vivo induction of AT at around P20 disrupted IPSC and EPSC integration in the LSO, so that 1 week later the AMPA receptor (AMPAR)‐EPSC decay was slowed and mRNA for GluA1 increased while GluA4 decreased. In contrast, GlyR IPSC and NMDAR‐EPSC decay times were unchanged. Computational modelling confirmed that matched IPSC and EPSC kinetics are required to generate mature interaural level difference functions, and that longer‐lasting EPSCs compensate to maintain binaural function with raised auditory thresholds after AT. We conclude that LSO excitatory and inhibitory synaptic drive matures to identical time‐courses, that AT changes synaptic AMPARs by expression of subunits with slow kinetics (which recover over 2 months) and that loud sounds reversibly modify excitatory synapses in the brain, changing synaptic function for several weeks after exposure. Lateral superior olive (LSO) principal neurons receive AMPA receptor (AMPAR) ‐ and NMDA receptor (NMDAR)‐mediated EPSCs and glycinergic IPSCs. Both EPSCs and IPSCs have slow kinetics in prehearing animals, which during developmental maturation accelerate to sub‐millisecond decay time‐constants. This correlates with a change in glutamate and glycine receptor subunit composition quantified via mRNA levels. The NMDAR‐EPSCs accelerate over development to achieve decay time‐constants of 2.5 ms. This is the fastest NMDAR‐mediated EPSC reported. Acoustic trauma (AT, loud sounds) slow AMPAR‐EPSC decay times, increasing GluA1 and decreasing GluA4 mRNA. Modelling of interaural intensity difference suggests that the increased EPSC duration after AT shifts interaural level difference to the right and compensates for hearing loss. Two months after AT the EPSC decay times recovered to control values. Synaptic transmission in the LSO matures by postnatal day 20, with EPSCs and IPSCs having fast kinetics. AT changes the AMPAR subunits expressed and slows the EPSC time‐course at synapses in the central auditory system.