Center PI: Malenka, Robert C. Principal Investigator (Project 2): Sdhof, Thomas/Malenka, Robert Summary Although long-term synaptic plasticity has been studied for half a century, the fundamental mechanisms that mediate process such as NMDA-receptor-dependent LTP remain largely unknown, and the biological significance of LTP is incompletely understood. Here, we propose a novel avenue to understanding LTP by focusing on our recent unexpected observation that two different postsynaptic cell-adhesion molecules, LRRTMs and neuroligins which both bind to presynaptic neurexins, are essential for normal LTP. The present project is guided by the hypothesis that understanding trans-synaptic signaling mediated by neurexin-based cell adhesion may provide insight into the coordinated structural changes and vesicular trafficking events that occur postsynaptically during LTP.
Four specific aims utilizing conditional knockout mice of LRRTMs and neuroligins are proposed to test this overall hypothesis.
Specific Aim 1 will examine how LRRTMs and neuroligins contribute to LTP, Specific Aim 2 will map candidate molecular interactions of LRRTMs and neuroligins that underlie their function in LTP, Specific Aim 3 will test the role of these interactions in LTP using replacement of endogenous with mutant proteins in conditional knockout mice, and Specific Aim 4 will test the behavioral significance of the function of LRRTMs and neuroligins especially in learning and memory, with the aim to develop tests of the role of LTP in memory that involve highly selective changes in only LTP. Together, these experiments will advance our understanding of the relation between trans-synaptic cell adhesion mediated by neurexins and their ligands and long-term plasticity, thus contributing not only insight into how synapses are formed and function, but also into how LTP is induced and expressed. Relevance In studying LRRTMs and neuroligins, the present project will not only shed light on how these central organizers of synapses contribute to long-term plasticity and on the mechanisms of such plasticity, but will also provide a basic understanding of the potential role of these proteins in neuropsychiatric disorders such as autism and schizophrenia to which these proteins have been linked genetically. PHS 398/2590 (Rev. 11/07) Page 1 Summary

Public Health Relevance

Center PI: Malenka, Robert C. Principal Investigator (Project 2): Sdhof, Thomas/Malenka, Robert Project Narrative The present project proposes to use an interdisciplinary approach that ranges from molecular manipulations to behavioral studies to examine the mechanism and behavioral significance of the function of LRRTMs and neuroligins, postsynaptic cell-adhesion molecules that are ligands of presynaptic neurexins, in long-term synaptic plasticity. Results from these experiments will not only provide insight into how synapses are formed, but also describe the behavioral role of long-term synaptic plasticity and provide a background for the involvement of these proteins in autism and schizophrenia, thus addressing 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)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Stanford University
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