Distance-dependent synaptic inhibition in hippocampal neuronal networks

GABA能抑制性细胞和多巴胺能兴奋性主细胞（PC）之间的突触相互作用在脑中的信息处理中起着基础作用。中间神经元轴突，特别是表达小清蛋白（PV）的体周抑制性中间神经元（PIIs）的轴突，密集分布在大距离上，通过其抑制性输出突触控制数千个目标PC的电活动。因此，它们对信息的处理和存储作出了显著的贡献。然而，在成熟的皮层中的IN输出信号是否均匀地分布在网络中以完全填充所提出的功能，在很大程度上是未知的。我们目前的数据表明，在齿状回（DG）的PII介导的抑制性输出信号并不像以前认为的那样一致地强烈和快速，而是高度异质性的。事实上，这种异质性在空间和时间上是有序的。我们表明，perisomatic抑制的功能特性取决于通信伙伴之间的轴突距离，强大和快速抑制近邻和较弱和较慢的抑制遥远的细胞。我们将这种突触特性称为距离依赖性抑制信号。在拟议的项目中，我们的目标是检查（1）这种形式的抑制信号是否是特定于PIIs或它是否更普遍地适用于其他已识别的中间神经元类型，如树突靶向中间神经元，通过执行四重记录从一个突触前中间神经元和几个靶细胞（主细胞和中间神经元）。我们将把这些调查的重点放在啮齿类动物DG的海马体的输入区域中起着至关重要的作用，转码丰富的多模态输入从内嗅皮层到一个正交稀疏代码的CA 3区。(2)我们的目的是研究神经元间介导的距离依赖性抑制的细胞和分子机制，通过应用多学科的方法，结合电生理学，形态学，免疫组织化学和2-光子（2 P）成像技术在急性海马切片制备。(3)我们将研究距离依赖性抑制是否被突触兴奋抵消。(4)我们将测试距离依赖性抑制是否支持处理的信息，通过检查其贡献的神经元网络中的快节奏的同步，特别是在伽马（g; 30-100 Hz）频率，并形成同步活跃的细胞组件之间的密切互动实验研究和计算神经元网络分析。考虑到中间神经元，特别是PV-PIIs在高级脑功能中的关键作用，以及它们与由其功能障碍引起的认知障碍的密切关系，我们相信这项工作将显着有助于更好地理解中间神经元和皮层信息处理中的突触非均匀性。

Synaptic interactions between GABAergic inhibitory cells, and glutamatergic excitatory principal cells (PCs) play a fundamental role in processing of information in the brain. Interneuron axons, in particular the ones of parvalbumin (PV)-expressing perisomatic inhibitory interneurons (PIIs), distribute densely over large distances controlling the electrical activity of thousands of target PCs by means of their inhibitory output synapses. They contribute thereby markedly to the processing and storing of information. However, whether IN output signalling in the mature cortex is homogeneously distributed in the network to full-fill the proposed functions, is largely unknown. Our current data indicate that PII-mediated inhibitory output signalling in the dentate gyrus (DG) is not uniformly strong and rapid as previously thought, but highly heterogeneous. Indeed, this heterogeneity is spatially and temporally ordered. We show that the functional properties of perisomatic inhibition depend on the axonal distance between communicating partners, with strong and fast inhibition to close neighbours and weaker and slower inhibition to distant cells. We term this synaptic property distance-dependent inhibitory signalling. In the proposed project we aim to examine (1) whether this form of inhibitory signalling is specific to PIIs or whether it is more generally applicable to other identified interneuron types such as dendrite targeting interneurons by performing quadruple recordings from one presynaptic interneuron and several target cells (principal cells and interneurons). We will focus these investigations on the rodent DG which plays a crucial role as input region of the hippocampus by transcoding the rich multimodal input from the entorhinal cortex into an orthogonalized sparse code for the CA3 area. (2) We aim to examine the cellular and molecular mechanisms underlying interneuron-mediated distance-dependent inhibition by applying a multidisciplinary approach which combines electrophysiological, morphological, immunhistochemical and 2-Photon (2P) imaging techniques in acute hippocampal slice preparations. (3) We will examine whether distance-dependent inhibition is counterbalanced by glutamatergic synaptic excitation. (4) We will test whether distance-dependent inhibition supports processing of information by examining its contribution to the synchronization of fast rhythms in neuronal networks, in particular at gamma (g; 30-100 Hz) frequencies, and the formation of synchronously active cell assemblies by a close interaction between experimental investigations and computational neuronal network analysis. Considering the crucial role of interneurons, in particular PV-PIIs in higher brain function, and their strong relation to cognitive disorders resulting from their malfunction, we believe that this work will markedly contribute to a better understanding of interneurons and synaptic non-uniformity in cortical information processing.