Although enormous progress has been achieved in understanding how synapses work, little is known about how synapses are formed, and how diverse synapse properties are specified. Recent work suggests that neurexins have a central role in synapse specification, and that mutations in genes encoding neurexins contribute to autism and schizophrenia. Neurexins are presynaptic cell-adhesion molecules that are essential for normal synapse function, interact with multiple of postsynaptic ligands which in turn have also been implicated in autism and schizophrenia, and are expressed in thousands of alternatively spliced, regulated isoforms. The overarching goal of the present project is to elucidate the basic cellular and circuit functions of neurexins in mice as a model organism in order to gain insight into how neurexins contribute to the ability of synapses to transmit information, and to promote the understanding of how impairments in neurexin functions predispose to neuropsychiatric disorders. The project proposes five specific aims, namely to elucidate the trans-synaptic protein interaction network mediated by neurexins (Specific Aim 1), to determine the experience-dependent patterns of neurexin alternative splicing in defined types of neurons at the single-cell level (Specific Aim 2), to elucidate the role of alternative splicing of neurexins at SS#4 (Specific Aim 3), to determine the relative functions of neurexins using cKO mice (Specific Aim 4), and to perform an initial definition of the mechanisms of neurexin function.
These specific aims will be pursued using an interdisciplinary combination of methods that prominently include mouse genetics, electrophysiology, gene expression studies, imaging, and protein chemistry.
The specific aims are complementary to each other, and their results will synergize in producing a description of neurexins that relates the interactions of neurexins with specific pre- and postsynaptic ligands to their neuronal cell type-specific and activity-dependent expression, their alternative splicing, and their diverse functions. In this manner, this project will not only contribute to our basic understanding of how synapses process information in neural circuits, but also provide insight into how neurexin dysfunction contributes to neuropsychiatric disorders.

Public Health Relevance

Major recent progress revealed that the presynaptic cell-adhesion molecules neurexins and their ligands are genetically linked to autism, schizophrenia, and other neuropsychiatric disorders, but the basic functions of these molecules and the consequences of their dysfunction are incompletely understood. In addressing these issues, the present project will illuminate the pathogenic mechanisms underlying these disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37MH052804-26
Application #
9632846
Study Section
Special Emphasis Panel (NSS)
Program Officer
Driscoll, Jamie
Project Start
2015-03-15
Project End
2020-02-29
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
26
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Stanford University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
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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
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Polepalli, Jai S; Wu, Hemmings; Goswami, Debanjan et al. (2017) Modulation of excitation on parvalbumin interneurons by neuroligin-3 regulates the hippocampal network. Nat Neurosci 20:219-229
Südhof, Thomas C (2017) Molecular Neuroscience in the 21st Century: A Personal Perspective. Neuron 96:536-541

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