Abstract：
Sound localization involves information analysis in the lateral superior olive (LSO), a conspicuous nucleus in the mammalian auditory brainstem. LSO neurons weigh interaural level differences (ILDs) through precise integration of glutamatergic excitation from the cochlear nucleus (CN) and glycinergic inhibition from the medial nucleus of the trapezoid body (MNTB). Sound sources can be localized even during sustained perception, an accomplishment that requires robust neurotransmission. Virtually nothing is known about the sustained performance and the temporal precision of MNTB-LSO inputs after postnatal day (P)12 (time of hearing onset) and whether acoustic experience guides development. Here we performed whole-cell patch-clamp recordings to investigate neurotransmission of single MNTB-LSO fibres upon sustained electrical stimulation (1-200 Hz/60 s) at P11 and P38 in wild-type (WT) and deaf otoferlin (Otof) knock-out (KO) mice. At P11, WT and KO inputs performed remarkably similarly. In WTs, the performance increased drastically between P11 and P38, e.g. manifested by an 8 to 11-fold higher replenishment rate (RR) of synaptic vesicles and action potential robustness. Together, these changes resulted in reliable and highly precise neurotransmission at frequencies ≤100 Hz. In contrast, KO inputs performed similarly at both ages, implying impaired synaptic maturation. Computational modelling confirmed the empirical observations and established a reduced RR per release site for P38 KOs. In conclusion, acoustic experience appears to contribute massively to the development of reliable neurotransmission, thereby forming the basis for effective ILD detection. Collectively, our results provide novel insights into experience-dependent maturation of inhibitory neurotransmission and auditory circuits at the synaptic level. KEY POINTS: Inhibitory glycinergic inputs from the medial nucleus of the trapezoid body (MNTB) to the lateral superior olive (LSO) are involved in sound localization. This brainstem circuit performs reliably throughout life. How such reliability develops is unknown. Here we investigated the role of acoustic experience on the functional maturation of MNTB-LSO inputs at juvenile (postnatal day P11) and young adult ages (P38) employing deaf mice lacking otoferlin (KO). We analysed neurotransmission at single MNTB-LSO fibres in acute brainstem slices employing prolonged high-frequency stimulation (1-200 Hz/60 s). At P11, KO inputs still performed normally, as manifested by normal synaptic attenuation, fidelity, replenishment rate, temporal precision and action potential robustness. Between P11 and P38, several synaptic parameters increased substantially in wild-type mice, collectively resulting in high-fidelity and temporally precise neurotransmission. In contrast, maturation of synaptic fidelity was largely absent in KOs after P11. Collectively, reliable neurotransmission at inhibitory MNTB-LSO inputs develops under the guidance of acoustic experience.
摘要：
声音定位涉及横向上橄榄（LSO）的信息分析，哺乳动物听觉脑干中明显的核。LSO神经元通过精确整合来自耳蜗核（CN）的谷氨酸能兴奋和来自梯形体内侧核（MNTB）的甘氨酸能抑制来衡量耳间水平差异（ILD）。即使在持续感知期间，声源也可以被定位，需要强大的神经传递的成就。几乎没有人知道出生后第12天（P）12天（听力发作时间）后MNTB-LSO输入的持续性能和时间精度以及声学经验是否指导发展。在这里，我们进行了全细胞膜片钳记录，以研究在野生型（WT）和聋哑otoferlin（Otof）敲除（KO）小鼠中P11和P38持续电刺激（1-200Hz/60s）时单个MNTB-LSO纤维的神经传递。在P11,WT和KO输入表现非常相似。在WT中，例如,P11和P38之间的性能急剧增加,例如表现为突触小泡的补充率(RR)高8至11倍和动作电位稳健性。一起,这些变化导致频率≤100Hz时可靠且高度精确的神经传递.相比之下,KO输入在两个年龄段都表现相似，暗示突触成熟受损。计算模型证实了经验观察结果，并为P38KO的每个释放位点建立了降低的RR。总之,声学经验似乎对可靠的神经传递的发展做出了巨大的贡献，从而形成有效ILD检测的基础。总的来说，我们的研究结果为在突触水平上的抑制性神经传递和听觉回路的经验依赖性成熟提供了新的见解.关键点：从梯形体（MNTB）内侧核到外侧上橄榄（LSO）的抑制性甘氨酸输入参与声音定位。这种脑干电路在一生中都能可靠地运行。这种可靠性如何发展是未知的。在这里，我们研究了使用缺乏otoferlin（KO）的聋哑小鼠在青少年（出生后P11天）和年轻成年年龄（P38）时声学经验对MNTB-LSO输入功能成熟的作用。我们使用延长的高频刺激（1-200Hz/60s）分析了急性脑干切片中单个MNTB-LSO纤维的神经传递。在P11，KO输入仍然正常执行，表现为正常的突触衰减，保真度，补货率，时间精度和动作电位鲁棒性。在P11和P38之间，一些突触参数在野生型小鼠中显著增加，共同导致高保真和时间精确的神经传递。相比之下,P11后的KO中基本上没有突触保真度的成熟。总的来说，抑制性MNTB-LSO输入的可靠神经传递在声学经验的指导下发展。
