Dept. of Cognitive Neurology, Hertie Institute, Univ. of Tübingen, Otfried Müller Str. 27, 72076 Tübingen, Germany.
J Neurophysiol. 2011 Nov;106(5):2653-61. doi: 10.1152/jn.00612.2011. Epub 2011 Aug 17.
Following hyperpolarizing inputs, many neurons respond with an increase in firing rate, a phenomenon known as rebound excitation. Rebound excitation has been proposed as a mechanism to encode and process inhibitory signals and transfer them to target structures. Activation of low-voltage-activated T-type calcium channels and the ensuing low-threshold calcium spikes is one of the mechanisms proposed to support rebound excitation. However, there is still not enough evidence that the hyperpolarization provided by inhibitory inputs, particularly those dependent on chloride ions, is adequate to deinactivate a sufficient number of T-type calcium channels to drive rebound excitation on return to baseline. Here, this issue was investigated in the deep cerebellar nuclear neurons (DCNs), which receive the output of the cerebellar cortex conveyed exclusively by the inhibitory Purkinje cells and are also known to display rebound excitation. Using cerebellar slices and whole cell recordings of large DCNs, we show that a novel piperidine-based compound that selectively antagonizes T-type calcium channel activity, 3,5-dichloro-N-[1-(2,2-dimethyl-tetrahydropyran-4-ylmethyl)-4-fluoro-piperidin-4-ylmethyl]-benzamide (TTA-P2), suppressed rebound excitation elicited by current injection as well as by synaptic inhibition, whereas other electrophysiological properties of large DCNs were unaltered. Furthermore, TTA-P2 suppressed transient high-frequency rebounds found in DCNs with low-threshold spikes as well as the slow rebounds present in DCNs without low-threshold spikes. These findings demonstrate that chloride-dependent synaptic inhibition effectively triggers T-type calcium channel-mediated rebounds and that the latter channels may support slow rebound excitation in neurons without low-threshold spikes.
在超极化输入后，许多神经元的反应是增加放电率，这种现象称为反弹兴奋。反弹兴奋被提议作为一种编码和处理抑制性信号并将其传递到靶结构的机制。激活低电压激活 T 型钙通道和随之而来的低阈值钙峰是支持反弹兴奋的机制之一。然而，仍然没有足够的证据表明抑制性输入（特别是依赖氯离子的输入）提供的超极化足以使足够数量的 T 型钙通道失活，以在返回基线时驱动反弹兴奋。在这里，在深部小脑核神经元（DCN）中研究了这个问题，这些神经元接收小脑皮层的输出，这些输出仅由抑制性浦肯野细胞传递，并且也已知显示出反弹兴奋。使用小脑切片和大 DCN 的全细胞记录，我们表明，一种新型的哌啶基化合物，3,5-二氯-N-[1-（2,2-二甲基四氢吡喃-4-基甲基）-4-氟-哌啶-4-基甲基]-苯甲酰胺（TTA-P2），选择性拮抗 T 型钙通道活性，抑制由电流注入以及由突触抑制引起的反弹兴奋，而大 DCN 的其他电生理特性则没有改变。此外，TTA-P2 抑制了在具有低阈值峰的 DCN 中发现的短暂高频反弹以及在没有低阈值峰的 DCN 中存在的缓慢反弹。这些发现表明，氯离子依赖性突触抑制有效地触发 T 型钙通道介导的反弹，并且后者通道可能支持没有低阈值峰的神经元中的缓慢反弹兴奋。
