Neural circuits are constantly modified in response to experience and changes in the environment, a phenomenon known as plasticity. While classical Hebbian plasticity is crucial to encode information, a different set of mechanisms, commonly referred to as homeostatic plasticity, are used by neurons to stabilize their activity in the face of perturbations that alter excitability. Homeostatic plasticity plays a critical role during activity-dependent development of neural circuits, and it is frequently distorted in common psychiatric disorders, including autism, mental retardation and schizophrenia. However, in contrast to Hebbian plasticity, the molecular underpinnings of homeostatic plasticity are largely unknown. We hypothesize that microRNAs (miRNAs), a recently discovered class of regulatory small non-coding RNAs, might have a prominent role in homeostatic plasticity by fine-tuning the expression of critical synaptic proteins. Using a large activity-regulated miRNA cluster as a paradigm, we plan to identify functionally important miRNAs during homeostatic plasticity in vitro and in vivo, to elucidate their mode of regulation and to determine the relevance of perturbed expression of these miRNAs for psychiatric disease. Towards these aims, we plan to use a battery of innovative approaches, including miRNA loss-of-function screening, biological target discovery, time-lapse fluorescence imaging of miRNA activity, genetic manipulation of mouse models of psychiatric disease and systemic brain delivery of miRNA mimics. This project has far reaching implications for our understanding of homeostatic mechanisms in brain development and disease, and could open up new avenues for the treatment of prominent psychiatric disorders that arise from defective neural homeostasis.