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-MDCN-P (02))
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
$439,753
Indirect Cost
$153,257
Name
Stanford University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Gokce, Ozgun; Stanley, Geoffrey M; Treutlein, Barbara et al. (2016) Cellular Taxonomy of the Mouse Striatum as Revealed by Single-Cell RNA-Seq. Cell Rep 16:1126-37
Martinelli, David C; Chew, Kylie S; Rohlmann, Astrid et al. (2016) Expression of C1ql3 in Discrete Neuronal Populations Controls Efferent Synapse Numbers and Diverse Behaviors. Neuron 91:1034-51
Zhang, Bo; Südhof, Thomas C (2016) Neuroligins Are Selectively Essential for NMDAR Signaling in Cerebellar Stellate Interneurons. J Neurosci 36:9070-83
Földy, Csaba; Darmanis, Spyros; Aoto, Jason et al. (2016) Single-cell RNAseq reveals cell adhesion molecule profiles in electrophysiologically defined neurons. Proc Natl Acad Sci U S A 113:E5222-31
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
Aoto, Jason; Földy, Csaba; Ilcus, Silviana Maria Ciurea et al. (2015) Distinct circuit-dependent functions of presynaptic neurexin-3 at GABAergic and glutamatergic synapses. Nat Neurosci 18:997-1007
Fuccillo, Marc V; Földy, Csaba; Gökce, Özgün et al. (2015) Single-Cell mRNA Profiling Reveals Cell-Type-Specific Expression of Neurexin Isoforms. Neuron 87:326-40
Anderson, Garret R; Aoto, Jason; Tabuchi, Katsuhiko et al. (2015) β-Neurexins Control Neural Circuits by Regulating Synaptic Endocannabinoid Signaling. Cell 162:593-606
Zhang, Bo; Chen, Lulu Y; Liu, Xinran et al. (2015) Neuroligins Sculpt Cerebellar Purkinje-Cell Circuits by Differential Control of Distinct Classes of Synapses. Neuron 87:781-96
Um, Ji Won; Pramanik, Gopal; Ko, Ji Seung et al. (2014) Calsyntenins function as synaptogenic adhesion molecules in concert with neurexins. Cell Rep 6:1096-109

Showing the most recent 10 out of 57 publications