Mental illness at the molecular level

Eric Nestler’s molecular approach to psychiatric disorders set off a firestorm in his department.

Eric Nestler created a stir when he joined the faculty in 1987 and put a sign on his door that read “Laboratory of Molecular Psychiatry.” Many in psychiatry, he said, took offense at the notion that psychiatry could be understood at the molecular level.
Eric Nestler created a stir when he joined the faculty in 1987 and put a sign on his door that read “Laboratory of Molecular Psychiatry.” Many in psychiatry, he said, took offense at the notion that psychiatry could be understood at the molecular level.
Rodger Slott

When Eric J. Nestler, Ph.D. ’82, M.D. ’83, HS ’87, joined Yale’s Department of Psychiatry in 1987, he ordered a sign for his research space that read “Laboratory of Molecular Psychiatry.”

“It was like a lightning rod,” he recalled. “A lot of people in psychiatry were offended because they believed that you can’t understand psychiatric phenomena at a molecular level.”

But Nestler relished his status as a contrarian whose research countered existing beliefs.

During his 13 years on the psychiatry faculty, where he was the Elizabeth Mears and House Jameson Professor of Psychiatry, Pharmacology, and Neurobiology and director of both the Abraham Ribicoff Research Facilities and the Division of Molecular Psychiatry, Nestler explored the molecular mechanisms of drug addiction and depression in animal models. His focus was on how drugs and stress alter brain pathways in ways that lead to long-lasting behavioral changes. “The main contribution that I’ve made is demonstrating a convergence among the fields of molecular biology, neuroscience, and psychiatry,” said Nestler. “A molecular understanding of certain psychiatric phenomena is possible, as we’ve demonstrated specifically for addiction and depression.”

Psychiatry, said Nestler, who is now at the Mount Sinai School of Medicine in New York, has often lagged behind other medical areas in understanding the molecular underpinnings of disease. This is due in large part to the extraordinary complexity of the brain. His work has helped to counteract this trend by using state-of-the-art molecular biology tools to define disease pathogenesis, thereby helping to reintegrate psychiatry into mainstream biomedical science. In recognition of his accomplishments, Nestler was elected to the Institute of Medicine in 1998 and the American Academy of Arts and Sciences in 2005. He was also awarded the Goldman-Rakic Prize by the National Alliance for Research on Schizophrenia and Depression in 2008.

Nestler arrived at Yale as an undergraduate in 1972, and he jokes that his long history at Yale made him one of the most Yale-degreed people around, “but not necessarily the wisest.” He came to Yale College from Long Island, eager to study chemistry and biology. Little did he know that this move would mark the beginning of a 27-year stretch at the university. While a junior at Yale College, a plucky Nestler convinced Paul Greengard, Ph.D., who taught psychiatry and pharmacology at Yale from 1968 to 1983, to let him undertake research in Greengard’s laboratory for his senior thesis. “The opportunity to work in the Greengard lab was one of the most important milestones of my career,” Nestler said. He so enjoyed his research with Greengard, who studied cell signaling mechanisms in the nervous system, that he continued his graduate work there.

For his doctoral thesis, Nestler studied the role of protein phosphorylation in the nervous system. “It was very hard work with a lot of frustrations but, in the end, a lot of successes. We had some nice papers and I felt I learned a lot and contributed something to the lab and the field.” Indeed, Nestler was involved in early work supporting the argument that phosphorylation is an important event in regulating cell function—a discovery that garnered Greengard the 2000 Nobel Prize in Physiology or Medicine. “My claim to fame is that my work was the first to show that this process could be regulated by nerve impulses—electrical activity in the brain—and neurotransmitters,” Nestler said. When it came time for Nestler to set up his own lab, he applied his study of these signaling mechanisms to clinical psychiatry, specifically focusing on addiction in well-established animal models.

In 2000 Nestler left Yale to become chair of psychiatry at the University of Texas Southwestern Medical Center at Dallas. During his tenure there, Nestler helped develop the psychiatry department’s basic and clinical research programs, increasing funding from the National Institutes of Health from $5 million to $20 million and recruiting many new faculty. At the same time, Nestler managed to maintain his own research program.

A year ago Nestler joined Mount Sinai, where, as the director of the Mount Sinai Brain Institute, chair of the Department of Neuroscience, and the Nash Family Professor of Neuroscience, he plans to help build a novel translational neuroscience research program. The return to the Northeast has also allowed Nestler and his wife, Susan De Renzo, M.P.H. ’79, to be closer to their three children, ages 19, 21, and 23, who had come back to Connecticut to attend college near where they grew up. (Nestler and De Renzo met during Friday afternoon happy hours at the medical school, and the two have been married for what Nestler describes as “28 wonderful years.”) De Renzo is a consultant for Hunter College and the City University of New York School of Public Health.

Looking back over his life’s accomplishments and his heterodox academic career, Nestler said, “I consider myself to be an extremely lucky person, both professionally and personally.”

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