Center PI: Malenka, Robert, Principal Investigator: Chen, Lu/Sdhof, Thomas (Project 3) Summary A long-standing question in the field of neuroscience is how plastic changes at synapses in a circuit enable learning, encode memory, and drive behavior. Compared to the progress made in relating Hebbian plasticity to animal learning, little is known about the behavioral significance of homeostatic synaptic plasticity. Based on the newly discovered signaling pathway involved in homeostatic synaptic plasticity ? the synaptic retinoic acid pathway, and building on the progress made in the past years, this study aims to deepen our understanding of homeostatic synaptic plasticity by further exploring the involvement of postsynaptic exocytosis machineries and trans-synaptic adhesion molecules in homeostatic synaptic plasticity. Moreover, taking advantage of the known molecular components uniquely involved in the homeostatic synaptic plasticity, the study will probe in vivo functional significance of homeostatic plasticity by applying state-of-art genetic tools in animal behavioral studies. Through close collaboration with other projects of the Center, this project hopes to provide conceptual advancement to our understanding of homeostatic synaptic plasticity and retinoic acid signaling. Relevance The candidate molecules investigated in this project have been implicated in Autism spectrum disorders. Dissecting their involvement in homeostatic synaptic plasticity and RA signaling and examining the functional impact on animal learning when homeostatic plasticity is compromised will further our understanding of circuit maladaptation underpinning mental illnesses. PHS 398/2590 (Rev. 11/07) Page 1 Summary

Public Health Relevance

Center PI: Malenka, Robert, Principal Investigator: Chen, Lu/Sdhof, Thomas (Project 3) Project Narrative This application proposes to use state-of-art genetic tools to explore the molecular basis as well as the in vivo function of retinoic acid-mediated homeostatic plasticity. In charactering the involvement of synaptic proteins that have been implicated in various neurological disorders in the context of homeostatic synaptic plasticity, and the contribution of homeostatic synaptic plasticity to the overall learning capacity of the organism, this application will contribute to a better understanding of the synaptic and circuit underpinning of mental illness, and thus address the goals of PAR-14-120. PHS 398/2590 (Rev. 11/07) Page 1 Project Narrative

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZMH1-ERB-L)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Stanford University
Domestic Higher Education
United States
Zip Code
Zhang, Zhenjie; Marro, Samuele G; Zhang, Yingsha et al. (2018) The fragile X mutation impairs homeostatic plasticity in human neurons by blocking synaptic retinoic acid signaling. Sci Transl Med 10:
Bhouri, Mehdi; Morishita, Wade; Temkin, Paul et al. (2018) Deletion of LRRTM1 and LRRTM2 in adult mice impairs basal AMPA receptor transmission and LTP in hippocampal CA1 pyramidal neurons. Proc Natl Acad Sci U S A 115:E5382-E5389
Südhof, Thomas C (2018) Towards an Understanding of Synapse Formation. Neuron 100:276-293
Li, Jie; Park, Esther; Zhong, Lei R et al. (2018) Homeostatic synaptic plasticity as a metaplasticity mechanism?-?a molecular and cellular perspective. Curr Opin Neurobiol 54:44-53
Sclip, Alessandra; Acuna, Claudio; Luo, Fujun et al. (2018) RIM-binding proteins recruit BK-channels to presynaptic release sites adjacent to voltage-gated Ca2+-channels. EMBO J 37:
Südhof, Thomas C (2017) Synaptic Neurexin Complexes: A Molecular Code for the Logic of Neural Circuits. Cell 171:745-769
Liu, Zhihui; Chen, Zijun; Shang, Congping et al. (2017) IGF1-Dependent Synaptic Plasticity of Mitral Cells in Olfactory Memory during Social Learning. Neuron 95:106-122.e5
Jiang, M; Polepalli, J; Chen, L Y et al. (2017) Conditional ablation of neuroligin-1 in CA1 pyramidal neurons blocks LTP by a cell-autonomous NMDA receptor-independent mechanism. Mol Psychiatry 22:375-383
Zhou, Qiangjun; Zhou, Peng; Wang, Austin L et al. (2017) The primed SNARE-complexin-synaptotagmin complex for neuronal exocytosis. Nature 548:420-425
Chew, Kylie S; Fernandez, Diego C; Hattar, Samer et al. (2017) Anatomical and Behavioral Investigation of C1ql3 in the Mouse Suprachiasmatic Nucleus. J Biol Rhythms 32:222-236

Showing the most recent 10 out of 65 publications