Dysbindin and the Mechanisms Controlling the Homeostatic Modulation of Presynaptic Neurotransmitter Release Nervous system function remains remarkably stable despite the many changes that occur during the development, maturation, and aging of the brain. There is increasing evidence that neurons are endowed with potent mechanisms that compensate for perturbations to their activity and maintain the stability of neural function within proper physiological ranges. Although these homeostatic properties have been demonstrated in a variety of systems from invertebrates to humans, the mechanisms that mediate these fundamental and complex processes are poorly understood. Using Drosophila as a model for homeostasis at the level of the synapse, we have recently demonstrated that the gene dysbindin is required for synaptic homeostasis. Interestingly, the human homolog of dysbindin (DTNBP1) has emerged as a primary susceptibility gene for schizophrenia. The overall objective of this proposal is to define the mechanisms through which Dysbindin modulates neural function and achieves the homeostatic control of synaptic stability. The initial aim will be to define the role of Snapin in synaptic function and homeostasis. Snapin has been shown to bind Dysbindin and separately to modulate the synaptic fusion machinery. Next, biochemical and live imaging approaches will be used to monitor and test the importance of the Snapin-Dysbindin interaction for the homeostatic modulation of presynaptic release. Finally, I will explore the role of other proteins that interact with Dysbindin and go on to search for new genes that are required for synaptic homeostasis. The training phase of this research will be performed at the University of California, San Francisco in the laboratory of Dr. Graeme Davis. In this environment at UCSF, I will enhance both my experimental skills as well as the skills necessary to become a successful independent researcher. My long term goal is to understand the molecular mechanisms that govern the homeostatic control of neural function and how dysfunction in this process may contribute to complex neurological and psychiatric disease. I am committed to researching these areas at an academic institution. Public Health Relevance: Dysbindin has emerged as a primary susceptibility gene for schizophrenia in humans. This proposal seeks to elucidate the role of Dysbindin in the homeostatic control of neural function and to search for new genes involved in this process. Together, these efforts have to potential to implicate synaptic homeostasis in the etiology of schizophrenia and other complex psychiatric diseases.

Public Health Relevance

Dysbindin has emerged as a primary susceptibility gene for schizophrenia in humans. This proposal seeks to elucidate the role of Dysbindin in the homeostatic control of neural function and to search for new genes involved in this process. Together, these efforts have to potential to implicate synaptic homeostasis in the etiology of schizophrenia and other complex psychiatric diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Transition Award (R00)
Project #
5R00MH092351-04
Application #
8411238
Study Section
Special Emphasis Panel (NSS)
Program Officer
Asanuma, Chiiko
Project Start
2010-09-10
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
4
Fiscal Year
2013
Total Cost
$198,288
Indirect Cost
$56,570
Name
University of Southern California
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Chen, Chun-Kan; Bregere, Catherine; Paluch, Jeremy et al. (2014) Activity-dependent facilitation of Synaptojanin and synaptic vesicle recycling by the Minibrain kinase. Nat Commun 5:4246
Frank, C Andrew; Wang, Xinnan; Collins, Catherine A et al. (2013) New approaches for studying synaptic development, function, and plasticity using Drosophila as a model system. J Neurosci 33:17560-8