Synapses are intercellular junctions that mediate neuronal communication, and likely involve many cell-adhesion molecules that connect pre- and postsynaptic neurons to each other. Neurexins are presynaptic cell-adhesion molecules that are essential for the formation of functional synapses, and for the specification of the properties of synapses. Neurexins are highly polymorphic due to extensive alternative splicing, interact with multiple postsynaptic cell-adhesion molecules, and are associated with autism-spectrum disorders and schizophrenia, which highlights their importance for synaptic circuits. However, how exactly neurexins function in synapses, and how this function is impaired in autism spectrum disorders and schizophrenia, remains unclear. In the present application, we propose four specific aims to examine how neurexins function in synapses.
These aims utilize a combination of mouse genetics, electrophysiology, biophysics, and protein chemistry to determine the general functions of different neurexin isoforms, to understand the biological significance of their alternative splicing, to characterize how neurexins interact with multifarious ligands in a tightly regulated manner, and to elucidate the specific significance of their interactions with various ligands. These experiments will provide a comprehensive exploration of neurexin function and the mechanisms involved in this function, and clarify how neurexins act in specifying synapse properties. The results of these studies will not only provide insight into synaptic function in general, but also advance our understanding of synaptic dysfunction in cognitive disorders such as autism and schizophrenia.

Public Health Relevance

Synapses mediate the communication between nerve cells in brain, and are impaired in cognitive diseases such as autism or schizophrenia. Synapses are formed by cell-adhesion molecules such as neurexins, which in recent studies have been implicated in schizophrenia and autism. In the present project, we will continue our long-term investigation of how neurexins function at synapses, and how impairments of their function leads to cognitive diseases. Results from this project will not only provide insight into how neurons communicate, but also promote our understanding of how such communication becomes dysfunctional in autism and schizophrenia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37MH052804-21
Application #
8603288
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Asanuma, Chiiko
Project Start
1994-09-30
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
21
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Stanford University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
City
Stanford
State
CA
Country
United States
Zip Code
94304
Südhof, Thomas C (2018) Towards an Understanding of Synapse Formation. Neuron 100:276-293
Seigneur, Erica; Polepalli, Jai S; Südhof, Thomas C (2018) Cbln2 and Cbln4 are expressed in distinct medial habenula-interpeduncular projections and contribute to different behavioral outputs. Proc Natl Acad Sci U S A 115:E10235-E10244
Li, Jingxian; Shalev-Benami, Moran; Sando, Richard et al. (2018) Structural Basis for Teneurin Function in Circuit-Wiring: A Toxin Motif at the Synapse. Cell 173:735-748.e15
Zhang, Bo; Gokce, Ozgun; Hale, W Dylan et al. (2018) Autism-associated neuroligin-4 mutation selectively impairs glycinergic synaptic transmission in mouse brainstem synapses. J Exp Med 215:1543-1553
Seigneur, Erica; Südhof, Thomas C (2018) Genetic Ablation of All Cerebellins Reveals Synapse Organizer Functions in Multiple Regions Throughout the Brain. J Neurosci 38:4774-4790
Südhof, Thomas C (2017) Synaptic Neurexin Complexes: A Molecular Code for the Logic of Neural Circuits. Cell 171:745-769
Chen, Lulu Y; Jiang, Man; Zhang, Bo et al. (2017) Conditional Deletion of All Neurexins Defines Diversity of Essential Synaptic Organizer Functions for Neurexins. Neuron 94:611-625.e4
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
Anderson, Garret R; Maxeiner, Stephan; Sando, Richard et al. (2017) Postsynaptic adhesion GPCR latrophilin-2 mediates target recognition in entorhinal-hippocampal synapse assembly. J Cell Biol 216:3831-3846
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

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