Lu Chen
Academic Appointments
Key Documents
Contact Information
- Academic Offices
Personal Information Email Tel (650) 725-2512Administrative contact Angela Woerz Administrative assistant Email Tel Work 650-724-5264
Professional Overview
Administrative Appointments
- Associate Professor, Stanford Institute of Neuro-Innovation and Translational Neuroscience (2011 - present)
- Associate Professor, Department of Psychiatry and Behavioral Science (2011 - present)
Honors and Awards
- MacArthur Fellowship, MacArthur Foundation (2005)
- Keck Distinguished Young Scholar in Medical Research, W. M. Keck Foundation (2005)
- Packard Fellow in Science and Engineering, David and Lucile Packard Foundation (2005)
- NARSAD Young Investigator Award, NARSAD (2005)
- Beckman Young Investigator Award, Beckman foundation (2003)
- NRSA Postdoc fellowship, NIH (2001)
Postdoctoral Advisees
Kristin Arendt, Subhashree Ganesan, Yu-Tien Hsu, Anthony Lau, Jessie Luoma, Zhenjie Zhang
Graduate & Fellowship Program Affiliations
Internet Links
Scientific Focus
Current Research Interests
The long-term goal of my research is to understand the cellular and molecular mechanisms that underlie synapse function during behavior in the developing and mature brain, and how synapse function is altered during mental retardation. In this broad research area, I am specifically interested in the homeostatic control of synaptic strength, the role of postsynaptic protein translation in this control, and the impairment of synapses in Fragile X syndrome that involves changes in postsynaptic protein translation and synaptic strength.
We recently discovered a role of all-trans retinoic acid (RA) in regulating synapse formation and synaptic strength, which we identified during studies of homeostatic synaptic plasticity. We found that RA is a potent activator of synaptic strength in mature neurons. Neuronal synthesis of RA is regulated by activity. When neuronal activity is blocked, RA synthesis is strongly stimulated. When applied directly, RA is sufficient to rapidly increase synaptic strength. Moreover, when we blocked RA synthesis in neurons, we abolished the increase in synaptic strength induced by activity blockade. Taken together, these results reveal a central role of RA in mediating activity blockade-induced increases in synaptic strength, and suggest that in adult brain, RA functions as a novel diffusible messenger that regulates synaptic transmission.
Subsequent experiments revealed that the synaptic effect of RA operates by stimulating the synthesis and insertion of new postsynaptic AMPA-receptors into existing synapses. What mediates the translational regulation function of RA? Combining electrophysiological, biochemical and ultrastructural approaches, we identified a novel role of the RA-receptor RARα in translational regulation. We found that RAR directly associates with specific RNA sequences in the 5UTR of target mRNAs, and represses their translation. RA, by binding to RAR, releases this translational repression, probably by inducing a conformational change in RAR that leads to its dissociation from mRNA. To our knowledge, this is the first characterized translational regulatory mechanism that operates in a ligand-gated fashion.
How does the RA-dependent translational regulation intersect with other known mechanisms involved in dendritic protein synthesis and synaptic plasticity? We have recently found that the Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein that regulates local protein translation in dendrites, is essential for increases in synaptic strength induced by RA or by neural activity blockade. Activity-dependent RA synthesis is maintained in Fmr1 knockout neurons, but RA-dependent activation of dendritic translation of AMPA-type glutamate receptors is impaired. Furthermore, we showed that the deficit in synaptic scaling in Fmr1 knockout neurons can be rescued by acute postsynaptic expression of FMRP, indicating that the role of FMRP is not developmental, but that it is part of the homeostatic synaptic machinery. Taken together, these findings identify an unexpected role for FMRP in regulating homeostatic synaptic plasticity downstream of RA. Our results raise the possibility that at least some of the symptoms of Fragile X syndrome, a form of mental retardation caused by loss of FMRP function, reflect impaired homeostatic plasticity and dysfunctional RA signaling, and suggest that modification of the RA-signaling pathway in homeostatic plasticity may be beneficial for treating this prevalent disorder.
Publications
- AMPA receptor/TARP stoichiometry visualized by single-molecule subunit counting. Proc Natl Acad Sci U S A. 2013; (13): 5163-8
- Chronic inactivation of a neural circuit enhances LTP by inducing silent synapse formation. J Neurosci. 2013; (5): 2087-96
- Conditional RARα knockout mice reveal acute requirement for retinoic acid and RARα in homeostatic plasticity. Front Mol Neurosci. 2012: 16
- Synaptic retinoic acid signaling and homeostatic synaptic plasticity. Neuropharmacology. 2012
- Acute knockdown of AMPA receptors reveals a trans-synaptic signal for presynaptic maturation. EMBO J. 2011; (8): 1577-92
- Decrease in calcium concentration triggers neuronal retinoic acid synthesis during homeostatic synaptic plasticity. J Neurosci. 2011; (49): 17764-71
Help