Dopamine-producing neurons are laid down relatively late in brain development, suggesting that they have an important role in regulating a range of brain functions. Indeed, they do, according to Anthony Grace, Ph.D., Distinguished Professor of Neuroscience and a professor of psychiatry and psychology at the University of Pittsburgh. Grace has been involved in translational research related to the dopamine system for over 30 years. His early work pioneered the mode of action of antipsychotic drugs, and the identification and characterization of dopamine-containing neurons, and he was the first to provide a means to quantify their activity state and pattern in a way that is the standard in the literature[1]. His current work involves the role of dopamine in anhedonia and affective disorders, the mode of action of ketamine and novel antidepressant drugs, and novel treatments for schizophrenia and its prevention. He is one of a handful of individuals that not only performs important basic research, but can integrate this work into testable models relevant to the human condition.
Dopamine is associated with reward-motivated behavior and its overproduction is associated with addiction. When dopamine-producing neurons are in a chronic state of hyperactivity, the nervous system is overly alert, according to Grace, who has suggested, with other scientists, that this state of heightened alert is responsible for the side effects experienced by schizophrenics – cognitive problems, hallucinations and emotional instability. Conversely, suppression of this system is associated with depression. Understanding how dopaminergic neurons are regulated ultimately will allow scientists to develop much more targeted, effective therapies either for both schizophrenia and depression.
In landmark work early in his career, Grace proposed that animals genetically predisposed to developing schizophrenia, when subjected to stress, go onto develop the disease[2]. But just how does this happen? According to Grace, it’s not just the dopamine-producing cells that are to blame. In fact, the delicate circuitry within the brain is damaged, leading to chronic imbalances in how dopamine-producing cells are regulated.
Dopamine-producing cells normally fire in a tonic, or rhythmic pattern. But they are regulated in large part by input from two parts of the brain – the hippocampus and the amygdala. The hippocampus revs up the dopaminergic cells in specific brain areas in response to stress, thereby normally enabling an animal to deal with a stressor, like a potential predator or bully. But the amygdala does the opposite, calming the dopamine-producing neurons and enabling the brain to recover from stress.
Schizophrenics have a chronically hyperactive hippocampus, and multiple circuits seem to break down, leading to a state in which the brain is hypersensitive to dopamine. This results in the deleterious effects these patients experience. Ultimately, we want to understand how brain circuitry is disrupted in disease so we can develop better ways to repair the circuits and restore health, according to Grace. It wouldn’t be advisable to give strong anti-psychotic drugs to young children with faulty brain circuitry that responds inappropriately to stress and potentially sets them up for schizophrenia. Rather, we need to develop interventions that reduce stress and thus the risk of developing this disorder. But what about those with established disease? In his animal model of schizophrenia, Grace is exploring the use of a tranquilizing drug that is highly selective for the hippocampus, thereby offering hope of alleviating symptoms without causing widespread side effects on the nervous system.
Grace received his Ph.D. from Yale University School of Medicine with Benjamin S. Bunney, Ph.D., and had postdoctoral training with Rodolfo Llinas, Ph.D., in the Department of Physiology and Biophysics at New York University School of Medicine. Grace has been honored with awards for his research, including the William K. Warren Award for Excellence in Schizophrenia Research; the Paul Janssen Schizophrenia Research Award and the Lilly Basic Scientist Award from the International College of Neuropsychopharmacology; the Efron Award and the Axelrod Award from the American College of Neuropsychopharmacology; the Gold Medal award from the Society of Biological Psychiatry; the Outstanding Basic Research award from the Schizophrenia International Research Society; as well as a NIMH MERIT award, a Distinguished Investigator award from the National Alliance for Research in Schizophrenia and Depression, and the Judith Silver Memorial Investigator Award from the National Alliance for the Mentally Ill. He was named a Fellow of the American Association for the Advancement of Science. He is also a past member of the governing council of the American College of Neuropsychopharmacology and the Schizophrenia International Research Society and is on the editorial board of numerous leading journals in the field. Grace has published more than 300 articles (H index 92) spanning basic and clinical research, and has been cited nearly 30,000 times.
The Importance of Interneurons
In his research, Grace discovered one key part of circuitry failure in schizophrenia – the absence of important interneurons. These cellular go-betweens connect dopamine-producing cells to other regulatory elements within the brain. He showed that an absence of interneurons in an animal model of schizophrenia led to hyperactivity in the hippocampus and thus, to symptoms of schizophrenia[1]. He also found that these interneurons are lost around the time of adolescence, leaving the brain vulnerable to developing the disease[2]. A more effective drug therapy for schizophrenia likely lies in our ability to restore interneuron regulation of normal activity within specialized circuits of the hippocampus, he theorizes.
Grace also postulates that interneuron dysfunction will inevitably be shown to have important roles in other brain diseases. (August 2016, Nature). Interneurons are the last component to be incorporated into the developing brain, he notes, and interneurons migrate to their final positions within the brain to stabilize excitatory neural networks that have already been laid down. Furthermore, interneurons are responsible for rhythmic activity in a number of important brain circuits, including those governing memory and higher cognitive functions. These important cells are also highly susceptible to damage in the developing animals, suggesting that they may be vulnerable to environmental toxins, which are thought to play a role in some disorders affecting circuits that regulate dopamine.
Fluorescence image shows normal interneuron levels in the hippocampus of rats (left) and reduced levels of these same neurons in animals exhibiting schizophrenic-like symptoms (right). Reducing the loss of these interneurons could potentially prevent the emergence of schizophrenia in animals and humans, according to Grace.