Area of Research
Synapses and Circuits, Neural Degeneration and Repair
Neurotransmission and mechanisms of neurodegeneration in basal ganglia and dopamine neurons.
Our lab explores synaptic connections that underlie learning as well as neurodegenerative and neurodevelopmental diseases that occur at these synapses.
In particular, we examine three-part synapses formed by excitatory cortical projections and modulatory midbrain dopamine projections that converge onto striatal neuron dendrites, resulting in the so-called striatal microcircuit. Changes in the state of this structure underlie behavioral reinforcement or "reward" including that associated with food, sex, and motor learning. The synapses are also the primary targets for reinforcement by drugs of abuse including cocaine, amphetamine, nicotine, and opiates. Alterations in the state of the synapses appears to underlie addiction and schizophrenic psychosis, while loss of the participating neurons causes Parkinson's and Huntington’s diseases.
The striatal microcircuit. We combine optical, electrophysiological, and electrochemical techniques to measure interactions between the cortical, midbrain, and striatal synaptic components. We found that dopamine selectively filters the activity of cortical terminals in a manner dependent on firing frequency, while glutamate released from the cortical terminals reciprocally inhibits the dopamine terminals, although with very different kinetics. Present efforts attempt to understand how these actions select particular sets of cortical-striatal connections to produce motor and habit learning, and how this is disrupted in Parkinson’s and other disorders. We are also examining precisely how drugs of abuse such as amphetamine and alcohol alter this circuit, leading to addiction and associated behaviors.
Dopamine does not elicit conventional postsynaptic currents, and so we have developed new techniques to record dopamine release. With Dalibor Sames’ laboratory in the Department of Chemistry, we introduced fluorescent false neurotransmitters, fluorescent neurotransmitter derivatives that can be used to measure dopamine uptake and release at individual synapses, and provide a first means to detect differences within populations of synapses. We also developed electrochemical techniques including amperometry at synaptic terminals that resulted in the first recordings of quantal release of transmitter from central synapses. This approach has led to the discovery that fusion pores formed by small synaptic vesicles can rapidly (4 kHz) flicker between open and closed states. A major current goal of the lab is to identify the mechanisms underlying this and other phenomena that alter quantal neurotransmitter release.
Mechanisms of CNS disorders. Parkinson’s Disease is a motor disorder resulting from the death of dopamine neurons. We have found that several causes of this disease converge on interference with protein and organelle degradation via autophagic pathways, and that dopamine in the neurons can itself exacerbate this toxicity via specific interactions with pathogenic mutant genes. More recent work elaborates new roles for the immune system on neuronal death in this and other neurodegenerative disorders.
Additional new work indicates that autism may also be related to disturbances in degradation, in this case due to a lack of normal synaptic pruning in childhood. Our data further suggest that this disorder may stem from an inhibition of autophagic turnover of targeted synapses, stemming from disturbances in mTOR mediated pathways in neurons and glia.
In both neurodegenerative and developmental diseases, we are using the lab’s novel basic findings to assist the design of a variety of therapeutic strategies for patients.
Rodriguez, P.C., Pereira, D., Lee, M., Borgkvist, A., Wong, M., Barnard, C., Zhang, H., Sames, D., Sulzer, D. (2013) A pH sensitive fluorescent dopamine transporter substrate resolves uptake and exocytosis at individual synapses. PNAS, in press.
Daniela Hernandez, Ciara A. Torres, Wanda Setlik, Carolina Cebrián, Eugene V. Mosharov, Guomei Tang, Hsiao-Chun Cheng, Nikolai Kholodilov, Olga Yarygina, Robert E. Burke, Michael Gershon, David Sulzer (2012). Regulation of presynaptic neurotransmission by macroautophagy. Neuron, 74:277-284.
Sulzer, D. (2011). How addictive drugs disrupt presynaptic dopamine neurotransmission. Neuron, 69:628-649.
Mosharov EV, Larsen KE, Phillips KA, Wilson K, Kanter E., Schmitz Y., Krantz D.E., Edwards R.H., Sulzer D. (2009) Interplay between cytosolic dopamine, calcium and alpha-synuclein causes selective death of substantia nigra neurons. Neuron, 30:218-29.
Gubernator, N.G., Zhang, H., Staal, R.G.W., Mosharov, E.V., Pereira, D., Yue, M., Balsanek, V., Vadola, P.A., Mukherjee, B., Edwards, R.H., *Sulzer, D., *Sames, D. (*corresponding co-authors) (2009) Fluorescent false neurotransmitters visualize dopamine release from individual presynaptic terminals. Science, 324:1441-1444.
Bamford, N.S., Zhang, H., Joyce, J.A., Scarlis, C.A., Harleton, E., Sulzer, D. (2008). Chronic methamphetamine induces reversible long-term depression at corticostriatal terminals. Neuron, 58:1-15.
Bamford, N.S., Schmitz, Y., Schmauss, C., Zakharenko, S.S., Zablow, L., Sulzer, D. (2004) Dopamine selects sets of corticostriatal synapses. Neuron, 42:653-663.
Cuervo, A.M, Stefanis, L., Fredenburg, R., Lansbury, P., Sulzer, D.(2004). Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305: 1292-1295
Bamford, N.S., Zhang, H., Schmitz, Y., Wu, N.P., Cepdea, C., Levine,M.S., Schmauss, C., Zakharenko, S.S., Zablow, L., Sulzer, D. (2004) Heterosynaptic dopamine neurotransmission selects sets ofcorticostriatal terminals. Neuron 42: 653-663