Our research focuses on uncovering the molecular mechanisms and investigating the functional impact of a form of non-Hebbian synaptic plasticity, namely homeostatic synaptic plasticity. In contrast to the self-reinforcing nature of Hebbian plasticity, homeostatic plasticity operates under different rules as a ?corrective? mechanism to prevent run-away Hebbian plasticity. Compared to Hebbian plasticity, the contribution of defective homeostatic synaptic plasticity to neuronal and behavioral phenotypes in neurodevelopmental disorders is virtually unexplored. Work from our labs in the past years show that retinoic acid (RA) signaling, a major signaling pathway mediating homeostatic synaptic plasticity, is severely impaired in the absence of FMRP expression, resulting in a lack of homeostatic plasticity in both mouse and human FXS neurons. Moreover, we demonstrate that under a more natural, enriched environment, compromised homeostatic synaptic plasticity in adult mice induces run-away Hebbian plasticity as manifested by greatly enhanced long-term potentiation (LTP) and diminished long-term depression (LTD). As a behavioral consequence, animals with defective homeostatic plasticity exhibit enhanced learning but reduced behavioral flexibility when raised in an enriched environment. Together, our work establishes a link between synaptic RA signaling, homeostatic plasticity and cognitive function, and suggests that impaired homeostatic plasticity may contribute to cognitive deficits in FXS. The goal of the proposed research project is to build upon this knowledge base, and establish a disease research platform from which translationally relevant FXS phenotypes at cellular and synaptic levels can be identified and their functional implication in cognitive function at behavioral level can be further explored in model organisms. To achieve this, we will use both a mouse FXS model and human cerebral organoids generated from human FXS patient cells, run parallel experiments at molecular and cellular levels, and identify shared phenotypes between the two model systems. We will then explore the impact of these shared phenotypes on learning and memory formation in behaving FXS mice, thus gaining further insight into how altered homeostatic synaptic plasticity may compromise cognitive function in human patients. Establishing such a platform for disease research will facilitate animal model-based drug discovery by focusing on treatment of phenotypes that are pertinent to human patients.
