Topographic map refinement and synaptic strengthening of a sound localization circuit require spontaneous peripheral activity
Topographic map refinement and synaptic strengthening of a sound localization circuit require spontaneous peripheral activity
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声音定位电路的地形图细化和突触强化需要自发的外周活动
DOI：
10.1113/jp277757
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Friauf E
中科院分区：
文献类型：
--
作者：
Müller NIC;Sonntag M;Maraslioglu A;Hirtz JJ;Friauf E
要点失去钙感受器奥托弗林会扰乱内毛细胞的神经传递。耳铁蛋白基因敲除小鼠(OtofKO)的中枢听觉核团在功能上丧失了神经支配，我们用幼年和成年OtofKO小鼠(出生后10-12天和P27-49天)分别作为自发活动缺乏和耳聋的模型。我们研究了外周活动对从斜方体内侧核(MNTB)到外侧上橄榄核(LSO)声音定位回路中突触细化的影响。MNTBin活体记录显示OtofKO的自发性尖峰和耳聋显著减少。青少年KO表现为突触消除和加强受损，表现为MNTB-LSO输入更广泛，MNTB-LSO地形图不精确，MNTB-LSO纤维较弱。这些障碍一直持续到青壮年。在年轻的成年野生型动物中，未检测到听力开始后的进一步功能细化。总的来说，仅限于外周蛋白丢失的活动剥夺在关键的听前阶段损害了MNTB-LSO的功能细化。摘要回路细化对于听觉脑干中声音定位通路的发展至关重要。在听前小鼠(出生后12天左右开始听力)，自发活动从外周传播到中枢听觉核团。在新生小鼠的斜方体内侧核(MNTB)到外侧上橄榄(LSO)的甘氨酸能投射处，大量的MNTB纤维支配着一个给定的LSO神经元。在P4和P9之间，MNTB纤维在功能上被消除，而剩余的纤维被加强。对P20后的MNTB-LSO电路精化知之甚少。此外，MNTB-LSO对仅限于外围的活动剥夺的改进在很大程度上是未被探索的。这就留下了相当大的知识鸿沟，因为先天耳聋患者经常会被剥夺，例如，在耳铁蛋白基因(OTOF)突变时。在这里，我们分析了幼年(P10-12)和年轻(P27-49)耳铁蛋白基因敲除(OtofKO)小鼠的MNTB-LSO精细化。MNTBin活体记录显示，在基因敲除(KO)中，自发活动和耳聋显著减少，证实了剥夺。由于RNA测序显示野生型的MNTB和LSO中没有Otofss，KOS中的OtoFloss是外周特有的。功能性去神经损害MNTB-LSO突触的消除和加强，这是通过谷氨酸去掉和电刺激来评估的。消除障碍导致MNTB-LSO地形图不精确。强度受损与每MNTB纤维的量子含量较低有关。在年轻的成年KO中，MNTB-LSO回路仍未精炼。野生型在P12之后似乎没有进一步的功能提炼。总而言之，我们为MNTB-LSO功能回路成熟提供了新的见解，该成熟过程由耳蜗特异性蛋白质控制。OtofKOS的中枢功能障碍可能对感音神经性听力损失患者有影响。
Key pointsLoss of the calcium sensor otoferlin disrupts neurotransmission from inner hair cells. Central auditory nuclei are functionally denervated in otoferlin knockout mice (OtofKOs) via gene ablation confined to the periphery.We employed juvenile and young adultOtofKO mice (postnatal days (P)10–12 and P27–49) as a model for lacking spontaneous activity and deafness, respectively. We studied the impact of peripheral activity on synaptic refinement in the sound localization circuit from the medial nucleus of the trapezoid body (MNTB) to the lateral superior olive (LSO).MNTBin vivorecordings demonstrated drastically reduced spontaneous spiking and deafness inOtofKOs.Juvenile KOs showed impaired synapse elimination and strengthening, manifested by broader MNTB–LSO inputs, imprecise MNTB–LSO topography and weaker MNTB–LSO fibres. The impairments persisted into young adulthood. Further functional refinement after hearing onset was undetected in young adult wild‐types.Collectively, activity deprivation confined to peripheral protein loss impairs functional MNTB–LSO refinement during a critical prehearing period.AbstractCircuit refinement is critical for the developing sound localization pathways in the auditory brainstem. In prehearing mice (hearing onset around postnatal day (P)12), spontaneous activity propagates from the periphery to central auditory nuclei. At the glycinergic projection from the medial nucleus of the trapezoid body (MNTB) to the lateral superior olive (LSO) of neonatal mice, super‐numerous MNTB fibres innervate a given LSO neuron. Between P4 and P9, MNTB fibres are functionally eliminated, whereas the remaining fibres are strengthened. Little is known about MNTB–LSO circuit refinement after P20. Moreover, MNTB–LSO refinement upon activity deprivation confined to the periphery is largely unexplored. This leaves a considerable knowledge gap, as deprivation often occurs in patients with congenital deafness, e.g. upon mutations in the otoferlin gene (OTOF). Here, we analysed juvenile (P10–12) and young adult (P27–49) otoferlin knockout (OtofKO) mice with respect to MNTB–LSO refinement. MNTBin vivorecordings revealed drastically reduced spontaneous activity and deafness in knockouts (KOs), confirming deprivation. As RNA sequencing revealedOtofabsence in the MNTB and LSO of wild‐types,Otofloss in KOs is specific to the periphery. Functional denervation impaired MNTB–LSO synapse elimination and strengthening, which was assessed by glutamate uncaging and electrical stimulation. Impaired elimination led to imprecise MNTB–LSO topography. Impaired strengthening was associated with lower quantal content per MNTB fibre. In young adult KOs, the MNTB–LSO circuit remained unrefined. Further functional refinement after P12 appeared absent in wild‐types. Collectively, we provide novel insights into functional MNTB–LSO circuit maturation governed by a cochlea‐specific protein. The central malfunctions inOtofKOs may have implications for patients with sensorineuronal hearing loss.
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影响因子：
5.5
作者：
Magnusson, AK;Kapfer, C;Koch, U
通讯作者：
Koch, U
正常和先天性耳聋小鼠听觉脑干神经元的超极化激活（Ih）电流
影响因子：
3.4
作者：
R. Leão;Katarina Svahn;A. Berntson;B. Walmsley
通讯作者：
B. Walmsley
听力的发展和对声音刺激的反应行为：行为研究11本章中的研究得到了德国研究协会（Eh 53/1-5 和 Ma 374/2.4）的支持。
影响因子：
3
作者：
G. Ehret
通讯作者：
G. Ehret
影响因子：
16.2
作者：
Clause A;Kim G;Sonntag M;Weisz CJ;Vetter DE;Rűbsamen R;Kandler K
通讯作者：
Kandler K
中枢神经系统抑制性末端树枝化的发育和特异性。
DOI：
10.1002/neu.480220805
发表时间：
1991
期刊：
Journal of neurobiology
影响因子：
--
作者：
Sanes,DH;Siverls,V
通讯作者：
Siverls,V