This application is the renewal application for our current R01 that funds the successful collaborative work of the Wernig and Sdhof laboratories. The goal of the previous funding period of this grant was to develop induced neuronal (iN) cell protocols to provide the proof-of-principle that cell biological phenotypes can be studied in human neurons carrying autism-associated mutations. We have accomplished this goal which allows us now to include iN cells into our portfolio of model systems to investigate synaptic molecules affected in and relevant for neuropsychiatric diseases. In this renewal application, we propose to now apply the technologies developed in the previous funding period and use it to actually study neuronal cell biology in human neurons. The goal of this renewal application is to understand the molecular functions of normal and mutant neuroligins including their sorting to specific synaptic specializations, the identification of their critical binding partners, their detiled role on synaptic modulation, and the mechanism of action of mutant forms of neuroligins found in autism. Neuroligins are critical synaptic cell-adhesion molecules localized as constitutive homo- or heterodimers at the post-synaptic membrane. Their large extracellular domain interacts with neurexins and potentially other presynaptic membrane proteins, their smaller intracellular domain with various postsynaptic scaffold proteins such as PSD-95. We will employ well-established and widely accepted mouse models to define functional neuroligin domains and interaction partners of normal and experimentally modified neuroligins. Most autism-associated neuroligin mutations are found in the X-chromosomal NLGN4 gene. The mouse Nlgn4, however, is not well conserved with a mere 51% sequence similarity on the protein level and is much lower expressed than Nlgn1-3, which questions the relevance of mouse studies for human disease. For this reason, we propose to utilize the human iN cell systems that we developed to investigate normal and mutant NLGN4 synaptic function. The combined Wernig and Sdhof laboratories provide the complementary expertise to make such experiments realistically feasible.

Public Health Relevance

Neuropsychiatric diseases, including autism spectrum disorders and schizophrenia, are debilitating brain diseases that affect the personality of people. At least a fraction of these diseases is caused by genetic dysfunction of a specific cell adhesion machinery located at synapses, the sites where nerve cells contact each other. This application seeks to investigate the molecular structure of this adhesion machinery which will lead to a better understanding of the disease mechanisms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH092931-06
Application #
8888299
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Panchision, David M
Project Start
2010-09-29
Project End
2020-01-31
Budget Start
2015-05-15
Budget End
2016-01-31
Support Year
6
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Stanford University
Department
Pathology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
Zhong, Lei R; Chen, Xin; Park, Esther et al. (2018) Retinoic Acid Receptor RAR?-Dependent Synaptic Signaling Mediates Homeostatic Synaptic Plasticity at the Inhibitory Synapses of Mouse Visual Cortex. J Neurosci 38:10454-10466
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:
Südhof, Thomas C (2018) Towards an Understanding of Synapse Formation. Neuron 100:276-293
Tanabe, Koji; Ang, Cheen Euong; Chanda, Soham et al. (2018) Transdifferentiation of human adult peripheral blood T cells into neurons. Proc Natl Acad Sci U S A 115:6470-6475
Chanda, Soham; Hale, W Dylan; Zhang, Bo et al. (2017) Unique versus Redundant Functions of Neuroligin Genes in Shaping Excitatory and Inhibitory Synapse Properties. J Neurosci 37:6816-6836
Seigneur, Erica; Südhof, Thomas C (2017) Cerebellins are differentially expressed in selective subsets of neurons throughout the brain. J Comp Neurol 525:3286-3311
Yang, Nan; Chanda, Soham; Marro, Samuele et al. (2017) Generation of pure GABAergic neurons by transcription factor programming. Nat Methods 14:621-628
Patzke, Christopher; Acuna, Claudio; Giam, Louise R et al. (2016) Conditional deletion of L1CAM in human neurons impairs both axonal and dendritic arborization and action potential generation. J Exp Med 213:499-515
Yi, Fei; Danko, Tamas; Botelho, Salome Calado et al. (2016) Autism-associated SHANK3 haploinsufficiency causes Ih channelopathy in human neurons. Science 352:aaf2669
Chanda, S; Aoto, J; Lee, S-J et al. (2016) Pathogenic mechanism of an autism-associated neuroligin mutation involves altered AMPA-receptor trafficking. Mol Psychiatry 21:169-77

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