David Sulzer
Encyclopedia
David Sulzer is a 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.
Sulzer claims 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."
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 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.
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
.
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
.
The Sulzer lab has published over 120 papers on this research. For his work, Sulzer has received awards from the McKnight Foundation
, the National Institute on Drug Abuse
, 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.
.
http://sulzerlab.org/publications.html
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
neuroscientist and Professor at Columbia University Medical Center
Columbia University Medical Center
Columbia University Medical Center is an academic medical center that includes Columbia University's College of Physicians and Surgeons, College of Dental Medicine, School of Nursing and Mailman School of Public Health...
in the Departments of Psychiatry
Psychiatry
Psychiatry is the medical specialty devoted to the study and treatment of mental disorders. These mental disorders include various affective, behavioural, cognitive and perceptual abnormalities...
, Neurology
Neurology
Neurology is a medical specialty dealing with disorders of the nervous system. Specifically, it deals with the diagnosis and treatment of all categories of disease involving the central, peripheral, and autonomic nervous systems, including their coverings, blood vessels, and all effector tissue,...
, and Pharmacology
Pharmacology
Pharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...
. Sulzer's lab investigates the interaction between the synapses of the cerebral cortex
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
and the basal ganglia
Basal ganglia
The basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas...
, including the dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
system, in habit formation, planning, decision making, and diseases of the system.
Sulzer claims in an interview on NOVA
Nova
A nova is a cataclysmic nuclear explosion in a star caused by the accretion of hydrogen on to the surface of a white dwarf star, which ignites and starts nuclear fusion in a runaway manner...
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
Nature Medicine
Nature Medicine is an academic journal publishing research articles, reviews, news and commentaries in the biomedical area, including both basic research and early-phase clinical research. Topics covered include cancer, cardiovascular disease, gene therapy, immunology, vaccines, and neuroscience...
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."
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
Neurotransmission
Neurotransmission , also called synaptic transmission, is the process by which signaling molecules called neurotransmitters are released by a neuron , and bind to and activate the receptors of another neuron...
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
Electrochemistry
Electrochemistry is a branch of chemistry that studies chemical reactions which take place in a solution at the interface of an electron conductor and an ionic conductor , and which involve electron transfer between the electrode and the electrolyte or species in solution.If a chemical reaction is...
technique known as amperometry
Amperometry
Amperometry in chemistry and biochemistry is detection of ions in a solution based on electric current or changes in electric current.Amperometry is used in electrophysiology to study vesicle release events using a carbon fiber electrode...
using microelectrodes in an approach previously used by Mark Wightman, a chemist at the University of North Carolina
University of North Carolina
Chartered in 1789, the University of North Carolina was one of the first public universities in the United States and the only one to graduate students in the eighteenth century...
, 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 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
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
.
Sulzer's lab, together with that of Dalibor Sames, a chemist at Columbia University
Columbia University
Columbia University in the City of New York is a private, Ivy League university in Manhattan, New York City. Columbia is the oldest institution of higher learning in the state of New York, the fifth oldest in the United States, and one of the country's nine Colonial Colleges founded before the...
, 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
Dale's principle
In neuroscience, Dale's Principle is a rule attributed to the English neuroscientist Henry Hallett Dale. The principle basically states that a neuron performs the same chemical action at all of its synaptic connections to other cells, regardless of the identity of the target cell...
that a neuron releases the same transmitter from each of its synapses.
Addictive Drugs
By introducing the "weak base hypothesis" of amphetamineAmphetamine
Amphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
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
Amphetamine
Amphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
and methamphetamine
Methamphetamine
Methamphetamine is a psychostimulant of the phenethylamine and amphetamine class of psychoactive drugs...
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
Autophagy
In cell biology, autophagy, or autophagocytosis, is a catabolic process involving the degradation of a cell's own components through the lysosomal machinery. It is a tightly regulated process that plays a normal part in cell growth, development, and homeostasis, helping to maintain a balance...
, and with Nigel Bamford of the University of Washington
University of Washington
University of Washington is a public research university, founded in 1861 in Seattle, Washington, United States. The UW is the largest university in the Northwest and the oldest public university on the West Coast. The university has three campuses, with its largest campus in the University...
, 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
Addiction
Historically, addiction has been defined as physical and psychological dependence on psychoactive substances which cross the blood-brain barrier once ingested, temporarily altering the chemical milieu of the brain.Addiction can also be viewed as a continued involvement with a substance or activity...
.
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 autophagyAutophagy
In cell biology, autophagy, or autophagocytosis, is a catabolic process involving the degradation of a cell's own components through the lysosomal machinery. It is a tightly regulated process that plays a normal part in cell growth, development, and homeostasis, helping to maintain a balance...
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
Substantia nigra
The substantia nigra is a brain structure located in the mesencephalon that plays an important role in reward, addiction, and movement. Substantia nigra is Latin for "black substance", as parts of the substantia nigra appear darker than neighboring areas due to high levels of melanin in...
, in methamphetamine neurotoxicity, and Huntington's disease. With Ana Maria Cuervo of Albert Einstein College of Medicine
Albert Einstein College of Medicine
Albert Einstein College of Medicine is a graduate school of Yeshiva University. It is a not-for-profit, private, nonsectarian medical school located on the Jack and Pearl Resnick Campus in the Morris Park neighborhood of the borough of the Bronx of New York City...
they showed that a cause of Parkinson's disease could be due to an interference with a chaperone-mediated autophagy
Autophagy
In cell biology, autophagy, or autophagocytosis, is a catabolic process involving the degradation of a cell's own components through the lysosomal machinery. It is a tightly regulated process that plays a normal part in cell growth, development, and homeostasis, helping to maintain a balance...
caused by the protein alpha-synuclein
Alpha-synuclein
Alpha-synuclein is a protein that, in humans, is encoded by the SNCA gene. An alpha-synuclein fragment, known as the non-Abeta component of Alzheimer's disease amyloid, originally found in an amyloid-enriched fraction, is shown to be a fragment of its precursor protein, NACP, by cloning of the...
.
The Sulzer lab has published over 120 papers on this research. For his work, Sulzer has received awards from the McKnight Foundation
McKnight Foundation
The McKnight Foundation is a philanthropic organization based in Minneapolis, Minnesota in the United States. The foundation's interests lie in the environment, the arts, community development, and other areas....
, the National Institute on Drug Abuse
National Institute on Drug Abuse
The National Institute on Drug Abuse is a United States federal-government research institute whose mission is to "lead the Nation in bringing the power of science to bear on drug abuse and addiction."-History:...
, and NARSAD
NARSAD
NARSAD, or National Alliance for Research on Schizophrenia and Depression, is a private, not-for-profit public charity. It is the largest donor-supported organization that supports research on brain and behavior disorders...
. 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 HoffmannRoald Hoffmann
Roald Hoffmann is an American theoretical chemist who won the 1981 Nobel Prize in Chemistry. He currently teaches at Cornell University in Ithaca, New York.-Escape from the Holocaust:...
.
Scientific Articles
scientific articles can be downloaded fromhttp://sulzerlab.org/publications.html
Interviews
- http://www.pdonlineresearch.org/news/2009-06/15/spotlight-qa-dr-david-sulzer
- http://www.youtube.com/watch?v=3u3wWg4ATik
- http://www.pbs.org/wgbh/nova/secretlife/scientists/dave-sulzer/
Links
- http://www.sulzerlab.org/
- http://www.neuroscience.columbia.edu/?page=28&bio=200
- http://sulzerlab.org/TrainingProgram.html
- http://corneliastreetcafe.wordpress.com/entertaining-science/