报告摘要：

　　Fragile-X syndrome (FXS), caused by inactivation of the FMR1 gene, is a prevalent neurodevelopmental disorder predisposing to intellectual disability. Impaired homeostatic synaptic plasticity and deficient cognitive functions are key features of FXS. In this talk, I will describe our recent findings regarding how alternative splicing of neurexin genes impact homeostatic plasticity under normal conditions, and how it may drive abnormal synaptic plasticity and cognitive deficiency in FXS.  Briefly, we show that neurexin splice site 4 (SS4) encodes a permissive/inhibitory code for homeostatic synaptic plasticity in the mouse hippocampus in a gene-specific manner. In the Fmr1 knockout, which models FXS, deletion of FMRP quantitatively shifts Neurexin-2 SS4 from inclusion (SS4+) to exclusion (SS4-). Strikingly, we find that the Nrxn2 SS4- variant selectively and robustly inhibits homeostatic synaptic plasticity, suggesting that dominant expression of Nrxn2-SS4- in Fmr1-deficient neurons modeling FXS may account for the impaired homeostatic synaptic plasticity in FXS. Indeed, restoring Nrxn2-SS4+ expression in Fmr1 knockout mice rescued homeostatic plasticity and reversed the impairment in contextual fear memory deficit. Thus, the loss of homeostatic plasticity in Fmr1-deficient neurons is at least in part caused by altered Nrxn2 alternative splicing, such that normalizing Nrxn2 alternative splicing restores homeostatic plasticity and reinstates contextual fear memory.

报告人简介：

　　Dr. Lu Chen earned her bachelor’s degree in Biology from the University of Science and Technology of China. She completed her PhD at the University of Southern California under the mentorship of Dr. Richard Thompson, studying cerebellar circuits and synaptic plasticity during learning and memory. As a postdoctoral fellow with Dr. Roger Nicoll at UCSF, she investigated glutamate receptor trafficking and contributed to the discovery of TARP proteins, key regulators of AMPA receptors. Dr. Chen joined UC Berkeley in 2003 and moved to Stanford University’s Department of Neurosurgery in 2011. Her current research examines how synapses and neural circuits function during behavior and how they are altered in neurological disorders. Her laboratory studies homeostatic synaptic plasticity, postsynaptic protein translation, retinoic acid signaling, and interactions between homeostatic and Hebbian plasticity. It also investigates Fragile X syndrome and spinal dorsal horn circuit changes underlying neuropathic pain. Her honors include the Beckman Young Investigator Award, Packard Fellowship, Keck Distinguished Young Scholar Award, and MacArthur Fellowship.