Information flow in the brain is mediated by transduction of electrical information into chemical information and back again at chemical synapses. Synapses are made up of crucial cellular machineries that orchestrate a balance of membrane traffic to and from the plasma membrane. Our goal is to develop detailed quantitative understanding of the synapse both in terms of physiological responses to action potential stimuli as well as the molecular underpinnings of its function. One of the most important functional elements is the voltage-gated calcium channel as it converts the electrical signal into a flux of calcium that drives neurotransmitter release in a highly non-linear fashion. We recently developed sensitive approaches that allow us to characterize key properties of these channels and the electrical signal that controls them in their native environment, the nerve terminal. The goal of this project is determine the molecular basis of key mechanisms that determine VGCC function.
The first aim will examine the mechanisms of a novel form of adaptive plasticity whereby changes in VGCC number at nerve terminals in turn changes the shape of the electrical signal (the action potential). These experiments make use of an emerging technology of genetically-encoded fluorescent voltage indicators that allow one to quantitatively measure the action potential waveform in the nerve terminal and how it is controlled.
Our second Aim will use another new technology allowing us to determine how long VGCCs typically stay resident in the active zone, whether they can recycle through an intracellular presynaptic compartment and how these dynamics are controlled by activity, calcium influx and a number of presynaptic proteins.
The third Aim will examine how different active zone proteins, in particular Munc13 and Rim1, control different functional and cell biological aspects of VGCC function at nerve terminals.

Public Health Relevance

Information flow in the brain is mediated by transduction of electrical information into chemical information and back again at chemical synapses. The functioning of the human brain relies on the careful orchestration of delivering neurotransmitter-laden vesicles to sites at nerve terminals where they can be used to deliver this chemical message on demand. Many known genetic mutations in diseases such as Parkinson's disease, migraine headache and schizophrenia are linked to proteins that control synapse function. Our work is aimed at understanding the machinery at a molecular level to better ensure the success of future therapies for these types of neuronal diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH085783-09
Application #
9379415
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Asanuma, Chiiko
Project Start
2009-04-01
Project End
2019-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
9
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
de Juan-Sanz, Jaime; Holt, Graham T; Schreiter, Eric R et al. (2017) Axonal Endoplasmic Reticulum Ca2+ Content Controls Release Probability in CNS Nerve Terminals. Neuron 93:867-881.e6
Calloway, Nathaniel; Gouzer, GĂ©raldine; Xue, Mingyu et al. (2015) The active-zone protein Munc13 controls the use-dependence of presynaptic voltage-gated calcium channels. Elife 4:
Baumgart, Joel P; Zhou, Zhen-Yu; Hara, Masato et al. (2015) Isoflurane inhibits synaptic vesicle exocytosis through reduced Ca2+ influx, not Ca2+-exocytosis coupling. Proc Natl Acad Sci U S A 112:11959-64
Hoppa, Michael B; Gouzer, Geraldine; Armbruster, Moritz et al. (2014) Control and plasticity of the presynaptic action potential waveform at small CNS nerve terminals. Neuron 84:778-89
Kim, Sung Hyun; Ryan, Timothy A (2013) Balance of calcineurin A? and CDK5 activities sets release probability at nerve terminals. J Neurosci 33:8937-50
Ariel, Pablo; Hoppa, Michael B; Ryan, Timothy A (2012) Intrinsic variability in Pv, RRP size, Ca(2+) channel repertoire, and presynaptic potentiation in individual synaptic boutons. Front Synaptic Neurosci 4:9
Ariel, Pablo; Ryan, Timothy A (2012) New insights into molecular players involved in neurotransmitter release. Physiology (Bethesda) 27:15-24
Hoppa, Michael B; Lana, Beatrice; Margas, Wojciech et al. (2012) ?2? expression sets presynaptic calcium channel abundance and release probability. Nature 486:122-5
Pan, Ping-Yue; Ryan, Timothy A (2012) Calbindin controls release probability in ventral tegmental area dopamine neurons. Nat Neurosci 15:813-5
Hempel, Chris M; Sivula, Michael; Levenson, Jonathan M et al. (2011) A system for performing high throughput assays of synaptic function. PLoS One 6:e25999

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