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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Driscoll, Jamie
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University of Texas Sw Medical Center Dallas
Schools of Medicine
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Chanaday, Natali L; Kavalali, Ege T (2018) Optical detection of three modes of endocytosis at hippocampal synapses. Elife 7:
Chanaday, Natali L; Kavalali, Ege T (2018) Presynaptic origins of distinct modes of neurotransmitter release. Curr Opin Neurobiol 51:119-126
Kavalali, Ege T (2018) Spontaneous neurotransmission: A form of neural communication comes of age. J Neurosci Res 96:331-334
Liu, Pei; Khvotchev, Mikhail; Li, Ying C et al. (2018) Copine-6 Binds to SNAREs and Selectively Suppresses Spontaneous Neurotransmission. J Neurosci 38:5888-5899
Schaukowitch, Katie; Reese, Austin L; Kim, Seung-Kyoon et al. (2017) An Intrinsic Transcriptional Program Underlying Synaptic Scaling during Activity Suppression. Cell Rep 18:1512-1526
Li, Ying C; Kavalali, Ege T (2017) Synaptic Vesicle-Recycling Machinery Components as Potential Therapeutic Targets. Pharmacol Rev 69:141-160
Crawford, Devon C; Ramirez, Denise M O; Trauterman, Brent et al. (2017) Selective molecular impairment of spontaneous neurotransmission modulates synaptic efficacy. Nat Commun 8:14436
Afuwape, Olusoji A T; Wasser, Catherine R; Schikorski, Thomas et al. (2017) Synaptic vesicle pool-specific modification of neurotransmitter release by intravesicular free radical generation. J Physiol 595:1223-1238
Darios, Frederic D; Jorgacevski, Jernej; Flašker, Ajda et al. (2017) Sphingomimetic multiple sclerosis drug FTY720 activates vesicular synaptobrevin and augments neuroendocrine secretion. Sci Rep 7:5958
Horvath, Patricia M; Kavalali, Ege T; Monteggia, Lisa M (2017) CRISPR/Cas9 system-mediated impairment of synaptobrevin/VAMP function in postmitotic hippocampal neurons. J Neurosci Methods 278:57-64

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