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Obituary—Erminio Costa, M.D. (1924-2009), University of Illinois at Chicago

Editor’s note: The following obituary honors Erminio Costa, known in schizophrenia research circles in particular for his postmortem findings of GABA system disruption, as well as his more recent research on possible epigenetic etiology. He was Professor of Psychiatry at the University of Illinois at Chicago. This obituary was written by his colleagues Dennis Grayson and Alessandro Guidotti.

Erminio (Mimo) Costa, an expert in the field of neuropsychopharmacology, died Saturday, 28 November 2009, from complications of multiple myeloma. Dr. Costa is survived by his wife Ingeborg Hanbaur and sons Michael and Max. His son Robert passed away on 1 September 2006 from pancreatic cancer.

Dr. Erminio Costa

Dr. Costa was born in Cagliari, Italy, and obtained an M.D. from the University of Cagliari, graduating magna cum laude in 1947. This was the start of an enduring career in the fields of pharmacology and neuroscience. He continued his studies at the University, attaining the rank of Associate Professor (in 1948) and Professor of Pharmacology by 1954. In 1956, Dr. Costa joined the Thudichum Research Laboratory in Galesburg, Illinois, and studied under the direction of Drs. Harold Himwich and Murray Aprison in the neurochemistry laboratory. It was here that he was first exposed to clinical psychiatry at a time when chlorpromazine and its analogues became the standard of treatment for patients with schizophrenia. It was also during this period his passion for experimental neuropsychopharmacology was born. While presenting his work at a national meeting in 1958, Dr. Costa first met Dr. Bernard B. Brodie, considered by many to be the father of modern pharmacology. Dr. Brodie subsequently recruited Dr. Costa to the National Institutes of Health, where he became first a staff member and then Deputy Chief of the National Heart Institute's Laboratory of Chemical Pharmacology at the National Institutes of Health (NIH). In 1965, Dr. Costa joined Columbia University in New York as Director of Pharmacology of the W. Black Center for the study of Parkinson disease and three years later was asked to return to NIH, where he founded and for 17 years directed the prestigious Laboratory of Preclinical Pharmacology (LPP) of the National Institutes of Mental Health at St. Elizabeth's Hospital in Washington, D.C.

In 1985 at the age of 61, Dr. Costa founded and became Director of the Fidia-Georgetown Institute for the Neurosciences (FGIN) and Professor in the Departments of Anatomy and Cell Biology and Pharmacology at Georgetown University, Washington, D.C. (1985-1994). Here, he recruited a handful of scientists with their own expertise to create a program that was truly multidisciplinary. While each Lab Director was in charge of a research program, Dr. Costa oversaw the efforts and directed an often multifaceted approach to experimental neuroscience. At its height, FGIN employed 65 scientists from all over the world. Prior to the advent of the Internet, Dr. Costa and his colleagues implemented a Neuroscience Fax newsletter which was transmitted across the globe in an effort to reinvent how neuroscience findings might be communicated on a faster time scale.

During his career, Dr. Costa mentored numerous young scientists and made significant contributions to the field of neuropharmacology. Along with Dr. Brodie and numerous other eminent scientists, Dr. Costa was one of the founding members of the American College of Neuropsychopharmacology. Along with Professor Philip Bradley, University of Birmingham England, he shared the Chief Editor position for the Journal Neuropharmacology for some 27 years. In 1982, Dr. Costa was elected to the National Academy of Sciences (U.S.), and he maintained an active presence. Dr. Costa always considered scientific dialogue and rigorous analysis of scientific data to be integral to the training of junior scientists and the driving force for experimental design. During this time, the “Monday morning” scientific meeting, at which current research was presented by a member of the staff, became a tradition that would be carried into the next 20 years of his career. In 1988, together with Nobel Prize Laureates Rita Levi-Montalcini and Gerald Edelman, Dr. Costa founded and directed The International School of Neuroscience in Praglia Abbey, Padua, Italy. This school brought cutting-edge neuroscientists to a large audience of graduate students to expose them to the newest advances in the field. In addition to his accomplishments as a leader in the field of neuropharmacology, he championed the cause of neuroscience as a field second to none and without international boundaries. In 1991, Dr. Costa organized the Symposium on Molecular Neurobiology, sponsored by the National Academy of Sciences (U.S.) and the Academy of Sciences (USSR), held in Kiev, USSR. This effort allowed for the exchange of research data between scientists of the Soviet Union and the United States to foster international dialogue between researchers with similar interests. During his years at NIMH and later as Director of Fidia Georgetown Institute for the Neurosciences, Dr. Costa organized numerous world-renowned symposia and lecture series (the FIDIA Research Foundation Award Lectures in Neuroscience and Fidia Research Foundation Symposium Series). For many years, these were held as symposia satellites to the Annual Meeting of the Society for Neurosciences. From 1991 until 1996, Dr. Costa was a representative of the U.S. National Committee for IBRO. He was the driving force in organizing the "IBRO-SANS-USNC International Neuroscience Course on Neurotransmitter and Receptors" held at Rhodes University, Grahamstown, South Africa (1996).

In 1994, Dr. Costa became McDonnell Visiting Professor in Neurology at Washington University in St. Louis, Missouri, and Director of the Center for Neuropharmacology at the Nathan S. Kline Institute (NKI) for Psychiatric Research, Orangeburg, New York. In 1996, Dr. Costa was approached by Dr. Boris Astrachan to direct a research program in the Department of Psychiatry at the University of Illinois Chicago (UIC). At age 72, Dr. Costa rose to the challenge and recruited a team of top scientists including his long-time friend and co-worker, Dr. Alessandro Guidotti. Dr. Costa focused on research into the causes of schizophrenia. His efforts were the first to provide experimental evidence that the origins of schizophrenia might be epigenetic in nature. From 1996 until recently, Dr. Costa directed the Psychiatric Research Institute at UIC, and his contributions revealed important insights into our understanding of this insidious disease.

Dr. Costa's enthusiasm and ability to translate scientific hypotheses into successful experiments were contagious for all his collaborators—more than 300 in 60 years, from countries such as China, Japan, Russia, Afghanistan, Pakistan, India, and Nigeria, to a large number of European and Middle Eastern countries. His students always, even years after they had left his laboratories and been appointed to prestigious university positions, greatly valued his mentorship. Dr. Costa had an exceptional lifelong scientific career completely dedicated to discovery in neuroscience. His leadership and fostering of international scientific exchange has had a great impact in modern neuroscience for which he will long be remembered. During his recent retirement party (21 October 2009), well over 100 scientists representing nearly every continent attended to honor their mentor. During his long career, Dr. Costa authored over 1,000 manuscripts in prestigious scientific journals. He will be fondly remembered by his former students, collaborators, and peers.

Scientific Accomplishments
Dr. Costa’s scientific achievements, of unique breadth and depth, stem from his innovative and rigorous approach to tackling scientific issues. Dr. Costa was recognized with numerous awards over the years for his contributions, which have always been at the forefront of research in neuroscience and particularly in neuropsychopharmacology. His pioneering studies on serotonin in the human brain (1958) have been and are still followed by numerous other researchers. These scientists subsequently confirmed his initial reports on the multiplicity of serotonin receptors. His studies on serotonin established that this neurotransmitter was a target for the action of antidepressant and antipsychotic drugs. He introduced mass fragmentography as an innovative method that allowed the study of neurotransmitter steady-state levels and turnover rate in discrete rat brain nuclei, an index of specific neuronal system activation. This opened a new path to probe the mechanism of action of psychotropic drugs in vivo. In the early 1970s, Dr. Costa revealed the role of cyclic AMP in the trans-synaptic induction of tyrosine hydroxylase via a cascade of molecular cytosolic and nuclear events triggered by the activation and nuclear translocation of protein kinase A. These studies were among the first to show a regulatory action of cyclic AMP in the transcriptional activation of a specific gene, and currently this mechanism is considered to play an important role in the pathophysiology of depression and in the mechanism of dependence on drugs of abuse. He first proposed and discovered that the GABAA receptor is the target of anxiolytic benzodiazepines (1974). From these pioneering studies, he explored the mechanisms of GABAA receptor allosteric modulation and regulation that led to the discovery of the molecular mechanisms underlying benzodiazepine tolerance and dependence. As it applies to benzodiazepines, endogenous peptides, and neurosteroids acting on the GABAA receptors, his demonstration of drugs acting as allosteric modulators was fundamental to our appreciation of the structural heterogeneity of GABAA receptors. In addition, in the past few years, this discovery was expanded as a conceptual framework to probe the regulation and pharmacology of receptors for other neurotransmitters.

Given the poor results and numerous side effects associated with current neuroleptics, during the last 15 years Dr. Costa dedicated his efforts to finding better pharmacological treatments for schizophrenia. Typical for him, he took an innovative path. He and his colleagues established that reelin, an extracellular matrix protein that controls the correct positioning of neurons in laminated structures of the brain, continues to be expressed in the telencephalon and hippocampus of adult mammals, where it is synthesized and secreted by GABAergic interneurons. Reelin binds to integrin receptors expressed in dendritic spine post-synaptic densities and as a result of this binding, increases protein synthesis locally in dendritic spines, thus implying that reelin plays a fundamental role in synaptic plasticity. In 1998, Dr. Costa and his collaborators discovered that reelin and the enzyme that makes GABA (GAD67) were downregulated in the brains of schizophrenia patients, a finding in line with the observed neuropil hypoplasticity and decrease in dendritic spine density in the cortex and hippocampus of these patients. Interestingly, those GABAergic neurons that show reduced expression of reelin and GAD67 also show an increased expression of a DNA-methylating enzyme (DNMT1). These findings suggest that the reelin and GAD67 downregulation in the brains of schizophrenia patients is associated with hypermethylation of the corresponding promoters of these genes, and furthermore, these studies point to the possibility that an epigenetic mechanism underlies schizophrenia morbidity. Indeed, animal experiments with valproate, an inhibitor of histone deacetylases that indirectly increases DNA demethylase activity, led Costa and colleagues to suggest that histone deacetylase inhibitors be tested in the treatment of schizophrenia, and further, that they might mitigate schizophrenia vulnerability in individuals at high risk by decreasing reelin and GAD67 promoter hypermethylation and restoring reelin and GAD67 expression.

Dr. Costa’s exceptional scientific career will have a great impact in modern neuroscience for years to come as he continues to be quoted in scientific journals and his investigations provide the basis for much current experimentation.—Dennis Grayson and Alessandro Guidotti, Department of Psychiatry, University of Illinois Chicago.

Donations for the Erminio Costa Memorial Lecture should be made payable to:
University of Illinois—Department of Psychiatry
Note: In memory of Dr. Erminio Costa

Mailing Instructions:
Carla R. Ross
Room 551, M/C 912
University of Illinois at Chicago
Department of Psychiatry
1601 W. Taylor
Chicago, IL 60612

Comments on News and Primary Papers
Comment by:  Artyom Tikhomirov
Submitted 2 December 2009 Posted 3 December 2009

My condolences. May he rest in peace. Let his outstanding...  Read more

View all comments by Artyom Tikhomirov

Comment by:  Lorna Role
Submitted 22 December 2009 Posted 23 December 2009

Erminio will be missed by many, including me. My first...  Read more

View all comments by Lorna Role
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