Closing In on the Cellular Culprits of Schizophrenia
(Philadelphia, PA) – The cause of schizophrenia
remains a mystery, despite the millions of dollars spent
trying to discover which genes play a role in its etiology.
In at least 10 populations around the world, a significant
association between schizophrenia and the gene for dysbindin
has been noted – making dysbindin the most highly
replicated schizophrenia-associated gene described to
date. Now, researchers at the University of
Pennsylvania School of Medicine are starting
to place where dysbindin fits in the pathway that leads
from a gene to a psychiatric disorder. Schizophrenia
affects between 1 to 2 percent of people worldwide during
their lifetime and about 2.2 million American adults
have schizophrenia in a given year.
Using quantitative immunohistochemistry in postmortem
brain tissue, the Penn investigators found that the
expression of dysbindin protein was reduced in more
than 80 percent of the patients with schizophrenia by
an average of 40 percent relative to matched healthy
controls.(Click on the thumbnail image above to view
the full-size photo). “This is among the most
significant findings I’ve seen yet in schizophrenia
postmortem research, and it represents a critical lead
for understanding schizophrenia,” says senior
author Steven Arnold, MD, Associate
Professor of Psychiatry and Neurology. The research
appears in the May issue of the Journal of Clinical
The scientists also found that, in the same brain regions
in which there was a decrease in dysbindin, there was
also an increase in the amounts of presynaptic glutamate
packets, or vesicles, and that these findings were highly
correlated. Synaptic vesicles form at the ends of nerve
cells and contain chemical neurotransmitters such as
glutamate. Neurons communicate with each other by releasing
neurotransmitters from these vesicles. The researchers
surmise that dysbindin affects the manufacture or breakdown
of these vesicles and, consequently, glutamate may not
be released properly – thus impairing communication
The abnormality was most prominent in the dentate gyrus
portion of the hippocampus. This area of the brain is
especially important for memory, which is known to be
impaired in schizophrenia. The study’s findings
were independently replicated, using two collections
of postmortem brain tissue, one maintained by Penn and
another by the Stanley Medical Research Institute.
“The next step is to understand what dysbindin
does in the brain,” explains Arnold. “We’ve
found that dysbindin abnormalities are part of schizophrenia,
but we need to know much more to translate this information
into practical knowledge to help patients. In other
words, we need to know what other proteins dysbindin
interacts with and whether it involves just glutamate
or other neurotransmitters like serotonin, dopamine
or GABA and how dysbindin affects the electrical activity
of the brain. And, are there medicines that alter dysbindin
expression in the brain?” To answer these and
other important questions, Arnold and colleagues are
currently collaborating with other researchers at the
University of Oxford in the United Kingdom.
“One of the most exciting parts of this story
is that the extensive work that has gone on in the genetics
of schizophrenia is finally starting to bear fruit in
terms of identifying specific genes that we can then
follow-up in the brain,” says Arnold. “Who
would have predicted that a protein that was first discovered
a few years ago by muscular dystrophy researchers could
have anything to do with schizophrenia? The genetics
studies pinpointed a link between dysbindin and schizophrenia.
This clue prompted us to investigate dysbindin in the
brain where we found that it is highly expressed and
highly abnormal in schizophrenia.”
Other Penn researchers collaborating on this work are
Konrad Talbot, Wess L. Eidem, Edward W. Thompson, Rachel
J. Smith, Chang-Gyu Hahn, John Q. Trojanowski, and Raquel
E. Gur, as well as Caroline L. Tinsley and Matthew A.
Benson from Oxford University. The research was supported
in part by the National Institute of Mental Health.
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