In central synapses, synaptobrevin2 (syb2, also called VAMP2) is the predominant synaptic vesicle SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) protein that interacts with the plasma membrane SNAREs SNAP-25 and syntaxin1 to execute exocytosis. However, while neurons lacking syb2 have a nearly complete absence of evoked neurotransmission, they still maintain significant levels of spontaneous neurotransmitter release. The physiological role of this residual spontaneous release after genetic deletion of syb2 has remained elusive. Recent studies have shown that alternative vesicular SNARE proteins such as VAMP4, VAMP7 (also called tetanus-insensitive or TI-VAMP) and Vps10p tail interactor 1 a (Vti1a) functionally diverge from syb2 and independently carry out spontaneous and some asynchronous neurotransmitter release. These studies demonstrated that these alternative vesicular SNAREs constitute molecular tags for independently functioning synaptic vesicle populations and provide a potential molecular basis for selective regulation of distinct forms of neurotransmitter release. In this application, we propose to examine the physiological impact of the forms of neurotransmitter release mediated by these alternative SNAREs. We will delineate how neurotransmitter release mediated by these alternative SNAREs directs neuronal signaling and synaptic efficacy via three Specific Aims. In the first aim, the synaptic scaling elicited by selective manipulation of spontaneous neurotransmitter release will be examined.
The second aim will focus on the postsynaptic Ca2+ signals elicited by spontaneous neurotransmitter release. Finally, the third aim will investigate the regulation of synaptic plasticity by selective manipulation of spontaneous neurotransmitter release in an intact synaptic circuit. Collectively, these complementary experiments will elucidate how spontaneous neurotransmission modulates neuronal function in a physiological network. Information attained from these studies will provide new insight to the synaptic substrates that may be affected by a number of in neuropsychiatric and neurological disorders including major depressive disorder, autism and schizophrenia.

Public Health Relevance

Our research focuses on the basic mechanisms that underlie the formation and function of synaptic connections in the brain. Synaptic vesicles within individual presynaptic nerve terminals are divided into distinct pools with respect to their relatie propensities for fusion. Our recent studies have demonstrated that the heterogeneous distribution of synaptic vesicle associated SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) proteins, in part, underlies this functional diversity among synaptic vesicles. In this project we will take advantage of this molecular information to selectively manipulate the function of distinct synaptic vesicle populations to elucidate their impact on neurotransmitter release and neuronal signaling. Information attained from these studies will provide new insight to the molecular synaptic substrates that may be affected by a number of neuropsychiatric and neurological disorders including major depression, mental retardation, autism and schizophrenia.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01MH066198-11
Application #
8734801
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Asanuma, Chiiko
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Neurosciences
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Kavalali, Ege T; Jorgensen, Erik M (2014) Visualizing presynaptic function. Nat Neurosci 17:10-6
Gideons, Erinn S; Kavalali, Ege T; Monteggia, Lisa M (2014) Mechanisms underlying differential effectiveness of memantine and ketamine in rapid antidepressant responses. Proc Natl Acad Sci U S A 111:8649-54
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Monteggia, Lisa M; Gideons, Erinn; Kavalali, Ege T (2013) The role of eukaryotic elongation factor 2 kinase in rapid antidepressant action of ketamine. Biol Psychiatry 73:1199-203
Nosyreva, Elena; Szabla, Kristen; Autry, Anita E et al. (2013) Acute suppression of spontaneous neurotransmission drives synaptic potentiation. J Neurosci 33:6990-7002
Monteggia, Lisa M; Kavalali, Ege T (2013) Scopolamine and ketamine: evidence of convergence? Biol Psychiatry 74:712-3
Raingo, Jesica; Khvotchev, Mikhail; Liu, Pei et al. (2012) VAMP4 directs synaptic vesicles to a pool that selectively maintains asynchronous neurotransmission. Nat Neurosci 15:738-45
Akhtar, M Waseem; Kim, Mi-Sung; Adachi, Megumi et al. (2012) In vivo analysis of MEF2 transcription factors in synapse regulation and neuronal survival. PLoS One 7:e34863
Ramirez, Denise M O; Khvotchev, Mikhail; Trauterman, Brent et al. (2012) Vti1a identifies a vesicle pool that preferentially recycles at rest and maintains spontaneous neurotransmission. Neuron 73:121-34

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