"We are seeing what appears to be the same sort of thing happening as a result of abnormal influences," said Greenough, who holds a Swanlund Endowed Chair at the University of Illinois at Urbana-Champaign. "It appears that in both Fragile X and schizophrenia patients, abnormalities of the plasticity processes are occurring, or maybe some other genetic mechanism is driving the molding of the brain in the wrong directions."
Fragile X syndrome is an inherited condition and the leading cause of mental retardation in males. Schizophrenia is a severe emotional disorder involving misperceptions of reality, delusions and hallucinations.
Greenough is studying both conditions. He and Illinois colleague I.J. Weiler were the first to report that the Fragile X protein that is missing in the syndrome is synthesized at synapses. Synapses are the connections through which nerve cells communicate. Brain exams of deceased Fragile X sufferers revealed that nerve cells in the cerebral cortex had an overabundance of long, malformed dendritic spines Ð the receiving part of the synapse.
Earlier this month in the journal Neuron (Feb. 6), Greenough's team, in collaboration with the University of Pennsylvania School of Medicine, reported the presence of the glucocorticoid receptor among numerous molecules found in messenger RNA of the Fragile X protein. The receptor is necessary for the regulation of circulating levels of adrenal corticosteroids. Closer evaluation showed the receptor is in cells and dendrites of the brains of normal mice but absent from the dendrites of mice modified to not produce the Fragile X protein.
This latter discovery supports earlier findings at Stanford University Medical Center and the University of Minnesota that there is a deficiency in corticocosteroid regulation after exposure to mild stress in children with Fragile X syndrome.
Greenough's latest findings on schizophrenia were announced at last year's annual meeting of the Society for Neuroscience. Greenough's doctoral student Ian M. Kodish announced that autopsies on deceased schizophrenics had unveiled abnormally stubby dendritic spines and fewer headed spines, which are needed for synapses to operate properly, than in typical brains.
Pathology often exacerbates the mechanisms the brain uses to adapt to the demands of the world, Greenough said in today's session on "The Effects of Early Experience on Brain and Brain Development."
"When the circumstances are abnormal, you get abnormal results," he said. "From plasticity to pathology, the basic notion is that by understanding basic mechanisms of brain plasticity we can better understand what is happening in some pathological cases."
At Illinois, Greenough has faculty appointments in psychology, psychiatry (College of Medicine), the Center for Advanced Study, the campus bioengineering program, the department of cell and structural biology and the department of molecular and integrative physiology. In his talk, Greenough outlined his comprehensive brain research involving mice and rats, but mostly he focused on his recent human disease research.
"An important aspect of the brain abnormality in Fragile X syndrome appears to arise from deficits in the normal developmental synaptic pruning process, arising from the absence of a functional gene," he said. Without the FMR1 gene, he said, the elimination of unnecessary synapses during normal development does not occur, leaving an abundance of misfiring synapses that merely create noise rather than serve communication.
"You have a lot of incompatible synapses. They are thin; their morphology is altered," he said. "These synapses are doing something, but they are probably very weak. In this syndrome, there is an abnormality that appears to affect the normal plasticity process that modifies the brain on the basis of information from outside."
In schizophrenia, Greenough said, "there appears to be a deficit or decline in dorsolateral prefrontal cortical synaptic connectivity combined with morphological abnormalities, suggesting abnormal plasticity at the level of individual synapses."
Greenough's findings don't run counter to the long-held view of what occurs in schizophrenia. Rather they approach the dominant idea of a neurotransmitter imbalance involving dopamine and/or serotonin -- the target of most drug-based treatments -- from a different perspective.
"The neurotransmitter abnormalities are thought to occur in the basal forebrain," Greenough said. "The differences we see, however, are in the prefrontal cortex, which has been implicated in schizophrenia as a result of functional imaging showing, for example, a hypoactivity of synapses. We are saying that there is abnormal wiring of the prefrontal neurons, which may initially arise from neurotransmitter abnormalities but which ultimately become a separate aspect, exacerbating the overall pathology."
Before detailing his work on Fragile X and schizophrenia, Greenough briefly described five fundamental points on plasticity gained from his animal research:
- As the brain develops, there is an overproduction of synapses followed by a pruning process that encodes information-rich material based on experiences. Brain plasticity is an orchestrated process involving not only neurons and synapses but also other components, including capillaries, astrocytes and oligodendrocytes.
- Changes involving plasticity are not confined to development, although effects of experiences may occur more rapidly in younger animals. Changes in brain organization in response to experience occur throughout life.
- While plasticity is orchestrated, different aspects of experience regulate different kinds of cellular changes. "If an animal does a lot of simple, repetitive exercises, it will get changes in blood vessels but not many changes in terms of synapses," he said. "If the animal is learning a skill or acquiring important information, synapses change dramatically while blood vessels do not."
- Soon-to-be-published work by a former postdoctoral student, Greenough said, shows that functional changes result from the presence of increased capillaries formed by exercising. Increases in capillaries are paralleled by increases in both resting blood flow and the reserve capacity to respond to oxygen demand by increasing blood flow.
- The duration of plastic changes can vary a lot. "Synapses when made seem to stay there for a long time in the development process," he said. "If you put an animal in a complex environment and take the animal out of it, you don't quickly take the complex environment out of the animal. There are limits, of course, but changes do stick around. Blood vessel changes, however, are very short lived. Synapses carry information that you may have had only one opportunity in life to acquire, whereas new blood vessels can be made in a few days."