Area of Research

Synapses & Circuits, Neural Degeneration & Repair

Specialization

Neurotransmission and mechanisms of neurodegeneration in basal ganglia and dopamine neurons.

RESEARCH THEME

Our lab explores synaptic connections that underlie learning as well as neurodegenerative 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, a.k.a. synaptic triad. 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. We are also examining precisely how drugs of abuse may alter this circuit.

Dopamine does not elicit conventional postsynaptic currents, and so we have adapted amperometry to directly record dopamine release, resulting 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 neurodegeneration. Parkinson’s Disease is a severe motor disorder resulting from the death of dopamine neurons. We found that redistribution of dopamine from the reducing environment of synaptic vesicles into the cytosol produces intracellular oxygen radicals (the cytosolic dopamine hypothesis) and that this process underlies amphetamine-mediated neurotoxicity. Similar steps underlie the biosynthesis of neuromelanin, the characteristic pigment of the neurons that die in Parkinson’s, via induction of a lysosomal/autophagic protein degradation pathway. These steps may initiate the disease, as we found that a particular autophagic degradation pathway breaks down the alpha-synuclein protein implicated in Parkinson’s pathogenesis, while disease-causing variant mutants of this protein block normal degradation. We are currently attempting to identify other substrates of this pathway that may underlie the specificity of neuronal death in this disease. In contrast, Huntington’s disease is a fatal motor disorder that results from death of the striatal neurons, and we are pursuing findings that suggest disturbed autophagic protein degradation may also underlie steps in the pathogenesis of that disorder.

SELECTED PUBLICATIONS

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-author) (2009) "Fluorescent false neurotransmitters visualize dopamine release from Iindividual 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 AM, Stefanis L., Fredenburg R., Lansbury P., Sulzer D. (2004). Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science, 305:1292-5.

Cuervo, A.M, Stefanis, L., Fredenburg, R., Lansbury, P., Sulzer, D.(2004). Impaired degradation of mutant alpha-synuclein bychaperone-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