The role of interneuron plasticity in the generation of fast local network oscillations

越来越多的证据表明，中间神经元（IN）的可塑性有助于许多脑区微回路的可塑性。然而，IN可塑性的功能重要性仍然未知。在这里，我们提出，持久的可塑性的IN兴奋是一个主要的机制，特别是在伽马（g）频率范围内（30-90 Hz）的振荡脑活动的调节。我们将专注于我们的研究在这个建议专门在快速尖峰的IN表达钙结合蛋白小白蛋白（PV）在三个脑区：海马CA 3，海马旁皮质的前下托和运动皮质的M1亚区。这种方法的目的是澄清在何种程度上突触可塑性在一个定义的IN类型可以归因于一个特定的神经元网络功能的大脑区域。这里研究的中心网络功能是快速网络振荡的产生。所有实验将使用细胞外和全细胞记录在小鼠相应脑区的急性脑切片制备物中进行。体外振荡活动将被诱导。沿着这些路线，我们可以在研究单位（RU）的第一个资助期内表明，CA 3中的体外g振荡在兴奋性突触处诱导长时程增强（LTP）到快速尖峰PV中间神经元（PVIs）。为了探索PVI LTP是否可以反过来增强g-振荡，我们在第一次诱导后1小时第二次诱导g-活性。我们发现了第二种g模式的增强。在随后的实验中，我们可以提供初步的证据，PVI LTP参与这种形式的“g振荡塑性”。这里的中心目的是深化PVI塑性和g振荡的这些可能的相互作用的机制分析，并证实这一假设。此外，我们还将这种分析扩展到前下托和M1。假设PVI可塑性和g-振荡的相互作用，我们将使用“g-振荡可塑性”作为论文，与我们的合作伙伴（TP 1 Bartos，TP 5 Wulff）合作，测试RU中的新分子工具及其对干扰PVI可塑性的影响。新的分子机制将被确定通过使用本论文的差异RNA测序实验，并确定PVI可塑性相关的上调转录本。最后，我们将利用这篇文章来确定已经失去PVI可塑性的转基因疾病模型。这一分析的结果将导致新的分子假说的PVI可塑性和支持新的干涉工具的发展。随后的可塑性和连接性分析有前途的动物模型，通过使用多膜片钳记录与TP 3维达密切合作，将确定可塑性规则的变化和形态学改变，除了在本地网络拓扑结构的变化。这里获得的结果可以指导计算实验（TP 9 Sprekeler）和M1（TP 6 Poulet）的体内记录。

Increasing evidence suggests that interneuron (IN) plasticity is contributing to the plasticity of micro-circuits in many brain regions. However, the functional importance of IN plasticity remains unknown. Here, we propose that long-lasting plasticity of IN excitation is a main mechanism regulating oscillatory brain activity especially in the gamma (g) frequency range (30-90 Hz). We will focus our research in this proposal exclusively on fast-spiking INs expressing the calcium binding protein parvalbumin (PV) in three brain regions: The hippocampal CA3, the presubiculum of the parahippocampal cortex and the M1 subregion of the motor cortex. This approach aims to clarify to which extent synaptic plasticity at one defined IN type could be attributed to a specific neuronal network function across brain regions. The central network function studied here is the generation of fast network oscillations. All experiments will be performed in acute brain slice preparations of the respective brain areas of mice using extracellular and whole-cell recordings. Oscillatory activity in vitro will be induced pharmacologically. Along these lines we could show in the 1st funding period of the research unit (RU) that in vitro g-oscillations in CA3 induce long-term potentiation (LTP) at excitatory synapses onto fast-spiking PV interneurons (PVIs). To probe whether PVI LTP could in turn enhance g-oscillations, we induced g-activity a second time 1h after the first induction. We discovered a potentiation of the second g-pattern. In subsequent experiments we could provide preliminary evidence that PVI LTP is involved in this form of ‘g-oscillation plasticity’. The central Aim here is to deepen the mechanistic analysis of these likely reciprocal interactions of PVI plasticity and g-oscillations and corroborate this hypothesis. In addition we will extent this analysis to the presubiculum and M1. Assuming the proposed reciprocal interactions of PVI plasticity and g-oscillations, we will use ‘g-oscillation plasticity’ as essay to test new molecular tools in the RU in collaboration with our partners (TP1 Bartos, TP5 Wulff) and their impact on interfering with PVI plasticity. The new molecular mechanisms will be identified by using this essay for differential RNA sequencing experiments and to identify PVI plasticity-related up-regulated transcripts. Finally, we will use this essay to identify transgenic disease models which have lost PVI plasticity. The results of this analysis will lead to new molecular hypothesis of PVI plasticity and support the development of new interference tools. Subsequent plasticity and connectivity analysis of promising animal models by using multi-patch-clamp recordings in close collaboration with TP3 Vida will identify changes of plasticity rules and morphological alterations in addition to changes in local network topology. The results obtained here may guide computational experiments (TP9 Sprekeler) and in vivo recordings in M1 (TP6 Poulet).