The importance of ventral midbrain dopamine (DA) synaptic activity is clear from its roles in motor and behavioral disorders, including drug dependence. These synapses contribute to the normal execution of motor sequences, learning, and habit formation by mediating short- and long-term plasticity in the basal ganglia. DA neuronal activity has been difficult to characterize by conventional technologies since the axons are extremely long and complex and do not make conventional ionotropic synapses that can be recorded by electrophysiology. We have thus developed new optical techniques, including fluorescent false neurotransmitters (FFNs) that provide the first means to examine neurotransmission at the level of individual synapses: the first two publications were part of the current grant cycle, and the requested continuation will introduce second generation FFNs that have important advantages over the first. In this work, we will first determine the signal by which DA axons grow and make synapses at the correct positions in the striatum: this appears to be triggered by glutamate inputs, apparently either from cortical inputs or from DA neurons themselves. These experiments will use one of the new FFNs, the first to work in neuronal cultures. Then we will identify the signals that make these DA synapses active: our Preliminary Results indicate that most DA terminals are "silent" and do not normally release neurotransmitter, but that this is modulated by a newly identified form of synaptic plasticity. Thi will use another new FFN that is well adapted for measuring DA transmission simultaneously with the synaptic vesicle fusion probe FM1-43. Finally, we will examine how DA and its loss in a unilateral Parkinson's disease model leads to selection of the correct corticostriatal synapses that underlie simple motor behaviors in the mouse, i.e., paw use to explore a novel environment, and a feeding behavior. To our knowledge, this will be the first time that particular synapses within a neuronal projection would be identified to underlie a behavior in the vertebrate CNS.

Public Health Relevance

This work is to determine how dopamine neurons grow to form the appropriate synaptic connections in the brain, how those synapses become active and inactive, and how they work to select the right synaptic connections to control voluntary motor behavior using a Parkinson's disease model. The importance of dopamine (DA) synaptic activity is clear from its roles in motor, learning and behavioral disorders, including drug addiction. DA neuronal activity has been difficult to characterize by conventional technologies and in this work we have thus developed new optical techniques, including fluorescent false neurotransmitters (FFNs) that provide the first means to examine neurotransmission at the level of individual synapses.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA007418-19A1
Application #
8604254
Study Section
Special Emphasis Panel (ZRG1-MDCN-R (02))
Program Officer
Pilotte, Nancy S
Project Start
1991-07-01
Project End
2018-08-31
Budget Start
2013-09-30
Budget End
2014-08-31
Support Year
19
Fiscal Year
2013
Total Cost
$317,563
Indirect Cost
$117,563
Name
Columbia University (N.Y.)
Department
Neurology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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Rodriguez, Pamela C; Pereira, Daniela B; Borgkvist, Anders et al. (2013) Fluorescent dopamine tracer resolves individual dopaminergic synapses and their activity in the brain. Proc Natl Acad Sci U S A 110:870-5
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Sulzer, David (2011) How addictive drugs disrupt presynaptic dopamine neurotransmission. Neuron 69:628-49
Lee, Minhee; Gubernator, Niko G; Sulzer, David et al. (2010) Development of pH-responsive fluorescent false neurotransmitters. J Am Chem Soc 132:8828-30
Mosharov, Eugene V; Larsen, Kristin E; Kanter, Ellen et al. (2009) Interplay between cytosolic dopamine, calcium, and alpha-synuclein causes selective death of substantia nigra neurons. Neuron 62:218-29
Schmitz, Yvonne; Luccarelli, James; Kim, Minji et al. (2009) Glutamate controls growth rate and branching of dopaminergic axons. J Neurosci 29:11973-81

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