Neurosteroid pregnenolone sulfate enhances glutamatergic synaptic transmission by facilitating presynaptic calcium currents at the calyx of Held of immature rats
Neurosteroid pregnenolone sulfate enhances glutamatergic synaptic transmission by facilitating presynaptic calcium currents at the calyx of Held of immature rats
复制标题
DOI：
10.1111/j.1460-9568.2006.05080.x
复制
发表时间：
2006-10-01
影响因子：
3.4
通讯作者：
Takahashi, Tomoyuki
中科院分区：
文献类型：
--
作者：
Hige, Toshihide;Fujiyoshi, Yoshinori;Takahashi, Tomoyuki
孕烯醇酮硫酸盐（PREGS）是一种内源性神经类固醇，广泛地从大脑中的神经元释放，并且被认为发挥增强记忆的作用。在兴奋性突触，PREGS促进递质释放，但其潜在机制尚不清楚。我们在大鼠脑干切片中的Held萼解决了这个问题，在那里直接从巨大的神经末梢进行全细胞记录是可行的。PREGS增强神经诱发的兴奋性突触后电流（EPSC），而不影响微型EPSC的振幅，表明其作用部位是突触前。在从肾盏神经末梢的全细胞记录中，PREGS通过加速其激活动力学和将半激活电压向负电位移动来促进Ca 2+电流。PREGS对突触前K+电流、静息电导和动作电位波形无影响。在突触前和突触后同步记录中，PREGS并没有改变突触前Ca 2+内流和EPSC之间的关系，这表明Ca 2+内流下游的胞吐机制并不参与其作用。PREGS易化神经末梢记录的Ba ~（2+）电流，也易化用重组N型或P/Q型Ca ~（2+）通道表达的HEK 293细胞记录的Ba ~（2+）电流，表明PREGS诱导的电压门控Ca ~（2+）通道（VGCC）易化既不是Ca ~（2+）依赖性的，也不是VGCC型特异性的。PREGS诱导的VGCC促进作用被PREGS清除剂（2-羟丙基）-β-环糊精从神经末梢的外部而不是内部施加所阻断。我们的结论是，PREGS通过外部作用促进突触前末梢的VGCC，从而增强递质释放。我们认为PREGS可能直接调节VGCC作用于其细胞外结构域。
Pregnenolone sulfate (PREGS) is an endogenous neurosteroid widely released from neurons in the brain, and is thought to play a memory-enhancing role. At excitatory synapses PREGS facilitates transmitter release, but the underlying mechanism is not known. We addressed this issue at the calyx of Held in rat brainstem slices, where direct whole-cell recordings from giant nerve terminals are feasible. PREGS potentiated nerve-evoked excitatory postsynaptic currents (EPSCs) without affecting the amplitude of miniature EPSCs, suggesting that its site of action is presynaptic. In whole-cell recordings from calyceal nerve terminals, PREGS facilitated Ca2+ currents, by accelerating their activation kinetics and shifting the half-activation voltage toward negative potentials. PREGS had no effect on presynaptic K+ currents, resting conductance or action potential waveforms. In simultaneous pre- and postsynaptic recordings, PREGS did not change the relationship between presynaptic Ca2+ influx and EPSCs, suggesting that exocytotic machinery downstream of Ca2+ influx is not involved in its effect. PREGS facilitated Ba2+ currents recorded from nerve terminals and also from HEK 293 cells expressed with recombinant N- or P/Q-type Ca2+ channels, suggesting that PREGS-induced facilitation of voltage-gated Ca2+ channels (VGCCs) is neither Ca2+ dependent nor VGCC-type specific. The PREGS-induced VGCC facilitation was blocked by the PREGS scavenger (2-hydroxypropyl)-beta-cyclodextrin applied from outside, but not from inside, of nerve terminals. We conclude that PREGS facilitates VGCCs in presynaptic terminals by acting from outside, thereby enhancing transmitter release. We propose that PREGS may directly modulate VGCCs acting on their extracellular domain.