First Floor Lecture Hall, Jianzan Building (Phase I)
Chinese Institute for Brain Research, Beijing
09:30-10:30 Monday，September 16th, 2019
Anthony Albert Grace, Ph.D.
Distinguished Professor of Neuroscience
Professor of Psychiatry and Psychology
Department of Neuroscience,
University of Pittsburgh
Dr. Minmin Luo
Substantial evidence demonstrates that schizophrenia involves a dysregulated dopamine system driven by overactivity in the hippocampus. Schizophrenia brains show a substantial loss of parvalbumin GABAergic interneurons in the hippocampus which likely drives the hyperactivity, leading to an over-responsive dopamine system. Our studies suggest that when the hippocampus is hyperactive the dopamine system is hyper-responsive to stimuli,which can underlie psychosis. A major question is why there is interneuron loss in the hippocampus. Parvalbumin interneurons early in life are susceptible to damage due to stress. In a developmental disruption model of schizophrenia, we found that prepubertally these rats are more anxious, hyper-responsive to stress, and show hyperactivity in the amygdala; furthermore relieving the stress early in life prevents the transition to “psychosis.” Thus, schizophrenia susceptibility may be due to heightened sensitivity to the deleterious effects of stress. Indeed, multiple stressors given during this sensitive period to normal rats leads to the schizophrenia phenotype. Moreover, elimination of the ability of the medial prefrontal cortex to regulate stress enables minor stressors to yield the schizophrenia phenotype. In contrast, multiple stressors given to adult rats result in a depression-like phenotype. However, if the critical developmental period is first re-opened in the adult rat via histone decarboxylase inhibition, the same stressors now yield a schizophrenia phenotype. This suggests that genetic predisposition does not cause schizophrenia, but instead causes the individual to be hypersensitive to the deleterious effects of stress. Moreover, stress susceptibility may be a common link in familial risk for schizophrenia and depression. Therefore, controlling stress early in life in susceptible individuals may be an effective means to prevent transition to schizophrenia later in life.
Dr. Grace has performed translational research on the dopamine system and schizophrenia for over 30 years. He pioneered the identification and characterization of dopamine-containing neurons, and was the first to quantify their activity state and pattern that is the standard in the literature. His lab developed the MAM developmental model of schizophrenia, and showed that the hyperdopaminergic state believed to be present in schizophrenia appears to be a direct result of overdrive of the dopamine system by the hippocampus, secondary to parvalbumin interneuron loss. His lab has advanced novel GABAergic drugs that may be effective in treating schizophrenia. He showed that MAM rats, like schizophrenics, are overstressed in puberty, and peripubertal diazepam treatment may prevent the transition to psychosis in susceptible individuals. Tony has won the Lilly Basic Scientist Award from the CINP, the Efron Award from the ACNP, a NIMH MERIT award, a Distinguished Investigator award from NARSAD, and fellow of the AAAS. Tony has made a substantial impact on the field (H index 80) spanning basic and clinical research. Tony is one of a handful of individuals that not only performs important basic research, but can to integrate this work into testable models relevant to the human condition.