Glycinergic Transmission in the Presence and Absence of Functional GlyT2: Lessons From the Auditory Brainstem.
Glycinergic Transmission in the Presence and Absence of Functional GlyT2: Lessons From the Auditory Brainstem.
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DOI：
10.3389/fnsyn.2020.560008
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发表时间：
2020
影响因子：
3.7
通讯作者：
Friauf E
中科院分区：
文献类型：
--
作者：
Brill SE;Maraslioglu A;Kurz C;Kramer F;Fuhr MF;Singh A;Friauf E
突触传递是由再摄取系统控制的，该系统降低突触间隙中的递质浓度并将递质再循环到突触前末梢。再摄取系统被认为是确保终端中的胞质浓度足以重新加载空突触囊泡（SV）。甘氨酸转运蛋白2（GlyT 2）的基因缺失导致抑制性神经传递严重中断，最终导致死亡。在这里，我们研究了GlyT 2在哺乳动物听觉脑干中抑制甘氨酸能突触的作用。这些突触的弹性，可靠性和精度，即使在持续的高频刺激时，内吞作用和SV的再填充可能大大有助于有效补充的易释放池（RRP）调整。在MNTB和LSO神经元（斜方体内侧核、外侧上级橄榄核）之间形成这种强健的突触。通过膜片钳记录，我们评估了对照组、GlyT 2敲除小鼠（科斯）和急性药理学GlyT 2阻断后的突触性能。通过计算模型，我们计算了在60秒的挑战和60秒的恢复期内的空释放位点的再占据率和RRP补充动力学。对照MNTB-LSO输入在50 Hz下维持高保真神经传递60 s，并非常有效地从突触抑制中恢复。在“马拉松实验”（20分钟内30，600次刺激）期间，RRP补充累积到1，260倍。相比之下，KO输入具有严重的损伤。例如，输入数量减少到~1（对照组为~4），这意味着MNTB-LSO微回路的大规模功能退化和GlyT 2在突触成熟过程中的作用。令人惊讶的是，在科斯中，神经传递并没有完全崩溃，因为输入仍然在50 Hz时补充其小RRP 80倍|60年代的挑战然而，他们在很长一段时间内完全没有这样做。在急性药理学GlyT 2失活后，突触性能保持稳健，与科斯形成鲜明对比。在马拉松实验中，RRP补充为865倍，仅比对照低约1/3。总的来说，我们的经验和建模结果表明，GlyT 2再摄取活性不是SV再循环途径中赋予MNTB-LSO突触不疲劳性的主导因素。我们推测，额外的甘氨酸来源，可能是反向转运蛋白Asc-1，有助于在这些高保真脑干突触的RRP补充。
Synaptic transmission is controlled by re-uptake systems that reduce transmitter concentrations in the synaptic cleft and recycle the transmitter into presynaptic terminals. The re-uptake systems are thought to ensure cytosolic concentrations in the terminals that are sufficient for reloading empty synaptic vesicles (SVs). Genetic deletion of glycine transporter 2 (GlyT2) results in severely disrupted inhibitory neurotransmission and ultimately to death. Here we investigated the role of GlyT2 at inhibitory glycinergic synapses in the mammalian auditory brainstem. These synapses are tuned for resilience, reliability, and precision, even during sustained high-frequency stimulation when endocytosis and refilling of SVs probably contribute substantially to efficient replenishment of the readily releasable pool (RRP). Such robust synapses are formed between MNTB and LSO neurons (medial nucleus of the trapezoid body, lateral superior olive). By means of patch-clamp recordings, we assessed the synaptic performance in controls, in GlyT2 knockout mice (KOs), and upon acute pharmacological GlyT2 blockade. Via computational modeling, we calculated the reoccupation rate of empty release sites and RRP replenishment kinetics during 60-s challenge and 60-s recovery periods. Control MNTB-LSO inputs maintained high fidelity neurotransmission at 50 Hz for 60 s and recovered very efficiently from synaptic depression. During 'marathon-experiments' (30,600 stimuli in 20 min), RRP replenishment accumulated to 1,260-fold. In contrast, KO inputs featured severe impairments. For example, the input number was reduced to ~1 (vs. ~4 in controls), implying massive functional degeneration of the MNTB-LSO microcircuit and a role of GlyT2 during synapse maturation. Surprisingly, neurotransmission did not collapse completely in KOs as inputs still replenished their small RRP 80-fold upon 50 Hz | 60 s challenge. However, they totally failed to do so for extended periods. Upon acute pharmacological GlyT2 inactivation, synaptic performance remained robust, in stark contrast to KOs. RRP replenishment was 865-fold in marathon-experiments, only ~1/3 lower than in controls. Collectively, our empirical and modeling results demonstrate that GlyT2 re-uptake activity is not the dominant factor in the SV recycling pathway that imparts indefatigability to MNTB-LSO synapses. We postulate that additional glycine sources, possibly the antiporter Asc-1, contribute to RRP replenishment at these high-fidelity brainstem synapses.
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DOI：
10.1523/jneurosci.5555-12.2013
发表时间：
2013-03-13
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Apostolides PF;Trussell LO
通讯作者：
Trussell LO
影响因子：
5.5
作者：
Bradaïa, A;Schlichter, R;Trouslard, J
通讯作者：
Trouslard, J
影响因子：
5.5
作者：
Fischer, Alexander U.;Mueller, Nicolas I. C.;Friauf, Eckhard
通讯作者：
Friauf, Eckhard
影响因子：
5.3
作者：
Gan Q;Watanabe S
通讯作者：
Watanabe S
影响因子：
4.2
作者：
Fratev, Filip;Miranda-Arango, Manuel;Sirimulla, Suman
通讯作者：
Sirimulla, Suman