Pioneers of brain-cell signaling earn Nobel

Three neuroscientists whose work has revealed molecular mechanisms by which brain cells communicate share this year’s Nobel Prize for Physiology or Medicine. Beyond opening a window to how memories form, their work has led to drugs for Parkinson’s disease and offered insight into how some antipsychotic drugs work.

“These discoveries have been crucial for an understanding of the normal function of the brain and how disturbances in [brain-cell signaling] can give rise to neurological and psychiatric diseases,” the Karolinska Institute in Stockholm stated in its award announcement.

The three investigators sharing the prize are Arvid Carlsson of the University of Gothenburg in Sweden, Eric R. Kandel of Columbia University, and Paul Greengard of Rockefeller University in New York City. While Nobel prizes often honor specific discoveries, neuroscientists consider this year’s honor a career-achievement award for a trio of widely respected pioneers.

“These are three giants of neuroscience,” says Solomon H. Snyder of Johns Hopkins University School of Medicine in Baltimore. “There are very few areas of neuroscience where you could be doing research without giving credit to one of these three guys.”

Each winner’s research centers on brain synapses, the sites at which a nerve cell sends signals to or receives them from another nerve cell. A single nerve cell in the brain can have many thousands of synapses connecting it with other cells.

Carlsson, Greengard, and Kandel “have been most responsible for changing our view of central [nervous system] synaptic function,” notes Charles F. Stevens of the Salk Institute for Biological Studies in San Diego.

Carlsson’s research has shed light on dopamine, a synaptic messenger that’s now known to regulate mood, movement, and even the way the brain responds to drugs and alcohol. Yet before Carlsson’s work in the late 1950s, scientists hadn’t recognized that the brain used this chemical directly for signaling. They believed that dopamine was simply the precursor of another neurotransmitter, noradrenaline.

Challenging that idea, Carlsson found dopamine, but not noradrenaline, in certain parts of the brain, including one that controls limb movement. This connection eventually led to the discovery that people with Parkinson’s disease, who suffer severe movement disabilities, lack dopamine-making neurons in key brain regions and that treatment with a dopamine precursor called l-dopa can reverse many of the condition’s symptoms.

Carlsson also deduced that several antipsychotic medications used for schizophrenia and other conditions work by blocking dopamine receptors, the cell-surface proteins that respond to the neurotransmitter. “Until you knew how the drugs act at a molecular level, you couldn’t design better ones,” notes Snyder.

Greengard’s research on synaptic signaling focused on events inside the nerve cell. When dopamine binds to its receptor, for example, a cascade of signals flows through the cell’s interior. This cascade, Greengard showed, depends on phosphorylation, a process in which an enzyme alters proteins by attaching phosphate molecules to them.

Kandel’s work investigated how synapses’ changing shape and function produce memory and learning. Because mammals’ brains are so complex, Kandel turned to a sea slug called Aplysia, which has only about 20,000 nerve cells. That risky move paid off.

Kandel, for example, showed that a protein called CREB helps the nervous system retain a memory or learned skill for a long period of time rather than just briefly. Drugs that manipulate this molecule may combat Alzheimer’s disease or boost the learning and memory of healthy people, Kandel has suggested.

“These guys are great scientists,” says Snyder. “I regard all three of them as my heroes.”