Neuronal synapses play pivotal roles in neural circuit functions. Abnormal synapse formation leads to numerous developmental diseases of the nervous system with cognitive and behavioral disabilities, including Down Syndrome, Angelman Syndrome, Fragile X Syndrome and Autism Spectrum Disorders. The mechanisms of how synapses form during development are poorly known. Understanding the basic mechanisms of synapse formation will be essential to understand the underpinnings of many birth defects in the nervous system for diagnosis and treatment. Several promising candidates for inducing synapse formation, such as the neuroligins and neurexins, are found not essential for synapse formation. Therefore, the question of synaptogenesis remains unsolved. Wnts have been shown to be able to regulate synapse formation in several embryonic neurons in hippocampus, cerebellum, spinal cord and the neuromuscular junction. Our preliminary results show that Wnt/planar cell polarity (PCP) signaling is required for excitatory synapse formation in dissociated hippocampal neuronal culture and in the neuromuscular junction in vivo. We propose to test the hypothesis that Wnt/PCP signaling is the central pathway, which directly assembles pre- and post-synaptic structures.

Public Health Relevance

Abnormal synapse formation leads to numerous developmental diseases of the nervous system with cognitive and behavioral disabilities, including Down Syndrome, Angelman Syndrome, Fragile X Syndrome and Autism Spectrum Disorders. Understanding the basic mechanisms of synapse formation will be essential to understand the underpinnings of many birth defects in the nervous system for diagnosis and treatment. Several promising candidates for inducing synapse formation, such as the neuroligins and neurexins, are not essential for synapse formation. Therefore, the question of synaptogenesis remains unsolved. We propose to characterize the role and mechanisms of Wnt/PCP signaling in formation of excitatory synapses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21MH099082-02
Application #
8547108
Study Section
Special Emphasis Panel (ZRG1-MDCN-G (02))
Program Officer
Asanuma, Chiiko
Project Start
2012-09-18
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$186,000
Indirect Cost
$66,000
Name
University of California San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093