Glial Cell Defects May Be Central to Bipolar Disorder.
PITTSBURGH -- Glial cells historically have been relegated to the role of supporting players in the central nervous system--a kind of passive "mind glue." But they may take center stage in the pathophysiology of bipolar disorder, Dr. Paul Harrison said at an international conference on bipolar disorder sponsored by the Western Psychiatric Institute and Clinic.
A better understanding of the relationship between glial defects, synaptic dysfunction, and disordered brain circuitry could suggest possibilities for novel treatments, said Dr. Harrison of the University of Oxford (England).
Brain imaging studies of bipolar disorder have led to several significant findings:
* Subcortical hyperintensities in deep white matter and basal ganglia--the type associated with vascular risk factors in other disorders.
* A reduction in cingulate gyrus size, compared with controls.
* A larger amygdala and smaller hippocampus.
"These are the first real clues about pathologic correlates," given that the changes occur in regions associated with emotional processing, he said.
These findings have helped guide studies of postmortem tissue, an "embryonic field" that has largely focused on a series of brains collected by the Stanley Foundation Research Programs. The series includes 15 brains each of controls, schizophrenic, and bipolar patients. The specimens are matched for age, sex, autopsy interval, and other parameters, and are free of gross neuropathology.
Several studies of the brain tissue have found decreased neuron and glial density in areas of the cingulate gyrus, as well as differences in glial density between hemispheres. A decrease in glial size and number also has been noted in the frontal cortex, Dr. Harrison said, noting that these changes have not been seen in the brains of schizophrenic patients.
The findings are of particular interest given recent developments in the understanding of glial cells and their function.
Unlike passive cells that provide little but structural support to neuronal tissue, glia are recognized as active partners in neurotransmission, affecting the development and plasticity of synapses. They represent part of a "metabolic unit" that regulates blood flow to the neuron.
The reductions in glial number and neuron size may suggest a relationship between defects of neuronal connectivity and mood disorder. Research to investigate this possibility has focused on synaptic protein genes that are a marker for synapses themselves, Dr. Harrison said at the meeting, also sponsored by the University of Pittsburgh.
Such studies have found reductions in synaptophysin, a marker for synaptic density; of growth-associated protein 43, a marker for synapse plasticity and turnover; and of complexin II, a marker for excitatory synapses. These are primarily in the cingulate gyrus of bipolar brains and are specific to bipolar disorder, unlike schizophrenia and major depressive disorder. The levels of all three proteins were inversely correlated with the duration of the illness, suggesting a harmful effect on the brain of chronic mood disorder.
Other studies have suggested similar pathology in the hippocampus, which--with the anterior cingulate gyrus--is an element of the limbic system that may be expected to be involved in mood disorders.
These findings suggest that altered neuronal connectivity is part of the anatomical substrate of bipolar disorder.
But causal and temporal relationships, which are unclear, raise the following questions:
* Is reduced glial density of genetic origin or the result of other pathologic processes, such as exposure to cortisol?
* How is the reduction in glial density related to developmental events?
In any case, therapeutic interventions that enhance synaptic maintenance and promote plasticity may be a worthwhile direction to pursue in terms of research, Dr. Harrison said. He noted that lithium--the most established treatment for bipolar disorder--appears to support the growth of new neurons--at least in animal models.
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|Publication:||Clinical Psychiatry News|
|Date:||Aug 1, 2001|
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