David Sulzer is an American neuroscientist and Professor at Columbia University Medical Center in the Departments of Psychiatry, Neurology, and Pharmacology. Sulzer's lab investigates the interaction between the synapses of the cerebral cortex and the basal ganglia, including the dopamine system, in habit formation, planning, decision making, and diseases of the system. His lab has developed the first means to optically measure neurotransmission, and has introduced new hypotheses of neurodegeneration in Parkinson's disease, changes in synapses that produce autism and habit learning. Additionally, as a musical artist, he is known as Dave Soldier.
Studies on synapses
The Sulzer laboratory has made contributions to understanding the basal ganglia and dopamine neurons, brain cells of central importance in translating will to action. They have introduced new methods to demonstrate how the synapses work, including the first means to measure the fundamental "quantal" unit of neurotransmitter release from central synapses and the first video means to observe release of neurotransmitter from individual synapses.
The fundamental unit of chemical neurotransmission is due to the "quantal release event", which is due to the fusion of synaptic vesicles with the plasma membrane, which provides for release of the encapsulated neurotransmitter from the synapse. Sulzer and colleagues reported the first direct recordings of quantal neurotransmitter release from brain synapses using an electrochemistry technique known as amperometry using microelectrodes in an approach previously used by Mark Wightman, a chemist at the University of North Carolina, to measure release of adrenaline from adrenal chromaffin cells.
Their experiments showed that the quantal event at dopamine synapses consisted of the release of about 3,000 dopamine molecules in about 100 nanoseconds. Further studies followed that showed that the quantal events could "flicker" due to extremely rapid opening and closing of the a synaptic vesicle fusion pore (at rates as high as 4,000 times a second) with the plasma membrane. This approach also demonstrated that the "size" of the quanta could be altered in numerous ways, for example by the drug L-DOPA, a drug so used to treat Parkinson's Disease.
Sulzer's lab, together with that of Dalibor Sames, a chemist at Columbia University, introduced "fluorescent false neurotransmitters", compounds that are accumulated like genuine neurotransmitters into neurons and synaptic vesicles. The use of fluorescent false neurotransmitters provides the first visual approach to observe neurotransmitter release and reuptake from individual synapses in video. These approaches are enabling important insights into the means by which particular synapses are selected or filtered to allow the brain to change and create new learning and memories.
Sulzer, along with his mentor Stephen Rayport, showed that the neurotransmitter glutamate is released from dopamine neurons, an important exception to the Dale's principle that a neuron releases the same transmitter from each of its synapses.
By introducing the "weak base hypothesis" of amphetamine action, means to measure amphetamine's effects on the quantal size of dopamine release, intracellular patch electrochemistry to measure dopamine levels in the cytosol, and providing real-time measurement of dopamine release by reverse transport, Sulzer's lab showed how amphetamine and methamphetamine release dopamine and other neurotransmitters and exert their synaptic and clinical effects.
The group extended these findings to show how methamphetamine neurotoxicity occurs, due to dopamine-derived oxidative stress in the cytosol followed by induction of autophagy, and with Nigel Bamford of the University of Washington, how these drugs activate long-term changes in the cortical synapses that project to the striatum: these changes, which they label "chronic postsynaptic depression" and "paradoxical presynaptic potentiation", the latter because methamphetamine selectively normalizes cortical synapses only of animal that previously were exposed to the drugs, appear to last for the life-time of the animal, and may underlie changes in the brain that lead to drug dependence and addiction.
Sulzer explains in an interview on NOVA that his interest in understanding mechanisms of addiction stem from crashing a talk by William Burroughs at Naropa Institute in 1980, where Burroughs claimed that new synthetic opiates would be so powerful that users would become addicts with a single dose. In an interview in Nature Medicine on his lab's discovery of the mechanism by which nicotine filters synaptic noise and can focus attention to tasks, he recalls his father's early death due to smoking, saying "if some idiot or drug company is going to twist things around, the only thing that would come out of [this research] that I'd be horrified by is if people used it to advocate smoking. I think it would be a real travesty if that happened."
Neurological & psychiatric disease
Sulzer and his lab extended their work on basal ganglia synapses to understanding the molecular events that control neurotransmission as well as the neuronal effects that underlie Parkinson's and Huntington's diseases, schizophrenia, drug addiction, and autism. They helped to introduce the now widespread notion that problems in protein and organelle degradation, particularly via autophagy by lysosomes was disturbed in neuronal disease, with early papers showing that this was implicated in the formation of neuromelanin, the pigment of the substantia nigra, in methamphetamine neurotoxicity, and Huntington's disease. With Ana Maria Cuervo of Albert Einstein College of Medicine they showed that a cause of Parkinson's disease could be due to an interference with a chaperone-mediated autophagy caused by the protein alpha-synuclein. His work indicates that a lack of normal pruning of synapses could underlie the development of autism, and that in turn may also my due to inhibited neuronal autophagy in patients, due to overactivation of the mTOR pathway during childhood and adolescence.
The Sulzer lab has published over 150 papers on this research. For his work, Sulzer has received awards from the McKnight Foundation, the National Institute on Drug Abuse (NIDA), and NARSAD. He runs the Basic Neuroscience NIH / NIDA (T32) training program for postdoctoral research in basic neuroscience at Columbia. He received a Ph.D. in Biology from Columbia University in 1988.
Entertaining Science series with Roald Hoffmann
Sulzer co-administers a long-running monthly Science & Art cafe series in Greenwich Village at the Cornelia Street Cafe, "Entertaining Science" with its founder, chemist and writer Roald Hoffmann.