Why it takes time to stay in balance: Defining the molecular timer of homeostatic plasticity and its power to regulate network activity and meta-plasticity

为了稳定运行，大脑中的神经元网络需要在兴奋和抑制之间保持良好的平衡(E/I平衡)。当个体在行为、睡眠或学习时，传入的信息流不断变化，从而使神经元网络中的神经元活动和突触权重永久改变。因此，为了维持E/I平衡，仅仅保持相应数量的兴奋性和抑制性突触是不够的。相反，为了避免网络在应对不断变化的输入时产生过度活跃或陷入沉默，有几种形式的所谓自我平衡可塑性(HP)已经到位。哺乳动物突触前介导的幽门螺杆菌(PreHP)的一个特点是诱导突触增强需要很长的时间。自从它被发现以来，已经描述了许多分子参与者和必要的结构重排。然而，这些研究的重点几乎完全集中在解决谷氨酸释放增强后发生的变化。在这里，我们讨论的假设是基于我们的初步发现，即前HP建立的缓慢时间过程是由于一系列事件的分子级联，其中每一步都依赖于前一步的成功完成。此外，我们的目标是从实验上解决内稳态增强和其他形式的可塑性之间的相互作用，最后，我们将研究慢性沉默PreHP对控制神经元网络全局活动的功能影响。综上所述，我们的实验结果将促进我们对突触前稳态可塑性建立的机制以及这种可塑性与神经元网络活动和元可塑性之间的相互作用的理解。

For stable operation, neuronal networks in the brain need to keep a well-tuned balance between excitation and inhibition (E/I-balance). While an individuum is behaving, sleeping or learning there is a continuously changing stream of incoming information such that neuronal activity and synaptic weights in neuronal networks are permanently altered. Therefore, to maintain the E/I-balance it is not sufficient to just keep a corresponding number of excitatory and inhibitory synapses. Rather, to avoid that networks generate excessive activity or fall silent in response to changing input several forms of so-called homeostatic plasticity (HP) are in place. One hallmark of mammalian presynaptically mediated HP (PreHP) is the long time it takes to induce synaptic potentiation. Since its discovery, many molecular players and necessary structural rearrangements have been described. However, the focus of these studies has almost exclusively been to resolve the changes that have occurred once glutamate release is potentiated. Here, we address the hypothesis which is based on our preliminary findings that the slow time course of PreHP establishment is due to a molecular cascade of events in which each step depends on the successful completion of the previous one. Furthermore, we aim to experimentally address the interplay between homeostatic potentiation and other forms of plasticity and finally, we will examine the functional impact of chronic silencing PreHP to control global activity of neuronal networks. In summary, the results of our experiments will advance our understanding of the mechanisms underlying the establishment presynaptic homeostatic plasticity as well as of the interplay between this form of plasticity and neuronal network activity and meta-plasticity.