Roscovitine differentially facilitates cerebellar glutamatergic and GABAergic neurotransmission by enhancing Cav2.1 channel-mediated multivesicular release
Roscovitine differentially facilitates cerebellar glutamatergic and GABAergic neurotransmission by enhancing Cav2.1 channel-mediated multivesicular release
复制标题
Roscovitine 通过增强 Cav2.1 通道介导的多泡释放来差异促进小脑谷氨酸能和 GABA 能神经传递
DOI：
10.1111/ejn.14771
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发表时间：
2020
影响因子：
3.4
通讯作者：
Konishi S.
中科院分区：
文献类型：
--
作者：
Satake S.;Konishi S.
突触囊泡胞吐作用由突触前末梢中几种电压门控钙通道亚型的Ca 2+内流触发。我们之前报道过，在大鼠小脑切片中，短暂间隔的成对脉冲刺激增加了颗粒细胞（GC）和分子层中间神经元（MLI）之间突触的Cav2.1（P/Q型）通道介导的多泡释放（MVR）。然而，Cav 2通道亚型如何参与单个轴突终末的MVR尚不清楚。因此，本研究旨在检查roscovitine对与浦肯野细胞（PC）接触的不同类型小脑突触的影响，因为该化合物已被证明可增强GC-MLI突触的Cav2.1通道介导的MVR。浴用roscovitine通过先前在GC-MLI突触中观察到的突触前机制显著增加了GC-PC突触的兴奋性突触后电流（EPSC）的振幅，而它对PC中攀爬纤维介导的EPSC产生了轻微影响。在MLI-PC突触，roscovitine通过增强多泡GABA释放增加抑制性突触后电流（IPSC）的振幅和衰减时间。当细胞外Ca 2+浓度（[Ca 2 +]e）降低时，roscovitine在增加GC-PC EPSCs方面的效果变差。相比之下，roscovitine能够在低[Ca 2 +]e中增加MLI‐PC IPSC。Cav2.1通道阻断剂ω-agatoxin IVA抑制了roscovitine诱导的对GC-PC EPSC和MLI-PC IPSC的易化作用。这些结果表明，roscovitine以依赖于Cav2.1通道介导的Ca 2+流入神经末梢的驱动力的方式增强GC-PC兴奋性突触的MVR，同时还通过Ca 2+不敏感机制促进MLI-PC抑制性传递。
Synaptic vesicle exocytosis is triggered by Ca2+influx through several subtypes of voltage‐gated calcium channels in the presynaptic terminal. We previously reported that paired‐pulse stimulation at brief intervals increases Cav2.1 (P/Q‐type) channel‐mediated multivesicular release (MVR) at glutamatergic synapses between granule cells (GCs) and molecular layer interneurons (MLIs) in rat cerebellar slices. However, it has yet to be determined how Cav2 channel subtypes take part in MVR in single axon terminal. This study therefore aimed at examining the effects of roscovitine on different types of cerebellar synapses that make contacts with Purkinje cells (PCs), because this compound has been shown to enhance Cav2.1 channel‐mediated MVR at GC‐MLI synapses. Bath application of roscovitine profoundly increased the amplitude of excitatory postsynaptic currents (EPSCs) at GC‐PC synapses by a presynaptic mechanism as previously observed at GC‐MLI synapses, whereas it caused a marginal effect on climbing fiber‐mediated EPSCs in PCs. At MLI‐PC synapses, roscovitine increased both the amplitude and decay time of inhibitory postsynaptic currents (IPSCs) by enhancing multivesicular GABA release. When extracellular Ca2+concentration ([Ca2+]e) decreased, roscovitine became less effective in increasing GC‐PC EPSCs. By contrast, roscovitine was able to augment MLI‐PC IPSCs in the low [Ca2+]e. The Cav2.1 channel blocker ω‐agatoxin IVA suppressed the roscovitine‐induced facilitatory actions on both GC‐PC EPSCs and MLI‐PC IPSCs. These results demonstrate that roscovitine enhances MVR at the GC‐PC excitatory synapses in a manner dependent on the driving force of Cav2.1 channel‐mediated Ca2+influx into the nerve terminal, while it also facilitates MLI‐PC inhibitory transmission via Ca2+‐insensitive mechanisms.