A molecular investigation of retinoic acid-dependent homeostatic synaptic plasticity

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Principal Investigator: Chen, Lu Summary Our research focuses on uncovering the molecular mechanisms 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 molecular and cellular mechanisms underlying homeostatic synaptic plasticity is much less understood, and their implication in neuropsychiatric disorders is largely 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 LTP and diminished LTD. As a behavioral consequence, animals with defective homeostatic plasticity exhibit enhanced learning but reduced behavioral flexibility when raised in 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 in the parent grant is to gain further understanding of the molecular and cellular mechanisms of RA-dependent homeostatic plasticity in the mouse brain. The project proposed in this administrative supplement further extends the experimental system to human neurons. Specifically, we will investigate whether aberrant alternative splicing of Neurexin genes underlies homeostatic synaptic plasticity phenotype in the FXS. Using the human brain organoid and assembloid models established in our lab, we will aim to validate in human neurons the findings from Specific Aim 1 of the mouse studies. PHS 398/2590 (Rev. 11/07) Page 1 Summary