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

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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.