Impact of dendritic inhibition on neuronal excitation and plasticity

哺乳动物大脑中的信号处理是基于兴奋和抑制之间的平衡。锥体神经元是新皮层和海马体的主要细胞，在它们的分支突起（称为树突）上接收大多数兴奋性和抑制性突触输入。然而，我们对这些信号如何沿着树突相互作用的了解很少，而且主要基于理论假设。早期的研究提出，抑制是高度局部的，当被放置在兴奋输入和细胞体细胞之间的“路径上”时，抑制是最有效的。相比之下，最近的理论研究表明，由于神经元树突的电紧张特性，越远的“偏离路径”抑制越强。此外，有人提出，抑制突触可能协同作用，在中央诱导比在抑制位点本身更大的抑制效应。这可能使一些位置良好的抑制性突触能够将整个树突亚区与体细胞分离。其他观察结果表明，抑制可能会调节峰值时间依赖的可塑性，这是一种突触可塑性的形式，取决于突触前和突触后活动的确切时间。然而，迄今为止，试图验证这些假设的实验研究得出了不一致的结果。这主要是由于缺乏适当的技术允许必要的空间和时间操作生理兴奋和抑制信号。此外，抑制性突触很难识别。在这项研究计划的范围内，我们将采用一种最新开发的技术，称为神经递质双色双光子释放，它可以在任何时空配置中精确激活兴奋性和抑制性突触。为了识别抑制性突触，我们将应用新的技术，允许荧光标记它们的突触前或突触后结构。通过将这些新工具与急性脑切片的电生理记录相结合，我们将能够通过实验验证以下假设：(i)“Off-path”抑制在抑制兴奋方面比“on-path”抑制更有效。（ii）相邻树突状分支上的多个抑制突触协同作用，集中抑制作用大于局部抑制作用。（iii）少数抑制性突触能够调节spike- time依赖性可塑性的分支特异性。通过使用最先进的光学和电生理技术，我们的研究结果有望大大提高我们对兴奋和抑制之间相互作用及其对突触可塑性影响的认识。最近的研究结果表明，树突抑制在感觉、学习和记忆中的重要性及其在神经系统疾病中的作用，强调了理解这些过程的重要性。

Signal processing in the mammalian brain is based on the balance between excitation and inhibition. Pyramidal neurons, the principle cells of the neocortex and hippocampus, receive the majority of excitatory and inhibitory synaptic inputs on their branched projections, called dendrites. However, our knowledge on how these signals interact along the dendrites is sparse and mainly based on theoretical assumptions. Early studies proposed that inhibition is highly local and most effective when placed "on-path" between the excitatory input and the soma of the cell. In contrast, more recent theoretical work suggested that due to the electrotonic properties of neuronal dendrites, more distal "off-path" inhibition is more powerful. In addition, it was proposed that inhibitory synapses may act cooperatively inducing a larger inhibitory effect centrally than at the inhibitory sites themselves. This might enable a few well-positioned inhibitory synapses to decouple an entire dendritic subregion from the soma. Other observations indicated that inhibition might regulate spike-timing-dependent plasticity, a form of synaptic plasticity that depends on the exact timing of pre- and postsynaptic activity.However, experimental studies trying to test these assumptions yielded inconsistent results so far. This is mainly attributable to a lack of appropriate techniques allowing the necessary spatial and temporal manipulation of physiological excitatory and inhibitory signals. Also, inhibitory synapses are difficult to identify.Within the scope of this research program, we will employ a recently developed technique, called two-color two-photon uncaging of neurotransmitters, which enables the precise activation of excitatory and inhibitory synapses in any spatiotemporal configuration. To identify inhibitory synapses, we will apply novel techniques allowing the fluorescent labeling of their pre- or postsynaptic structures. By combining these new tools with electrophysiological recordings in acute brain slices, we will be able to experimentally test the following hypotheses:(i) "Off-path" inhibition is more effective at dampening excitation than "on-path" inhibition.(ii) Multiple inhibitory synapses on adjacent dendritic branches act cooperatively exerting a larger inhibitory effect centrally than locally.(iii) A few inhibitory synapses are able to regulate branch-specificity of spike-timing-dependent plasticity.By using state-of-the-art optical and electrophysiological techniques our results are expected to considerably advance our knowledge of the interplay between excitation and inhibition and its effect on synaptic plasticity. The significance of understanding these processes is emphasized by recent results demonstrating the importance of dendritic inhibition in sensation, learning and memory and its involvement in neurological diseases.