of the studies, published in the March issue of Nature
Neuroscience, researchers examined DISC1's role in forming
connections between nerve cells. Numerous studies have suggested
that schizophrenia results from abnormal connectivity. The
fact that symptoms typically arise soon after adolescence,
a time of massive reorganization of connections between nerve
cells, supports this idea.
began their study by surveying rat nerve cells to see where
DISC1 was most active. Unsurprisingly, they found the highest
DISC1 activity in connections between nerve cells. To determine
what DISC1 was doing in this location, the researchers used
a technique called RNA interference to partially shut off
DISC1 activity. Consequently, they saw a transient increase
and eventual reduction in size and number of dendritic spines,
spikes on nerve cells' branch-like extensions that receive
input from other nerve cells.
how DISC1 regulates dendritic spine formation, the researchers
studied which brain proteins interact with the protein expressed
by the DISC1 gene. They identified one, called Kal-7, which
earlier studies suggested is critical for proper dendritic
spine formation. Further experiments suggested that the DISC1
protein acts as temporary holding place for Kal-7, binding
it until it can be released to trigger a molecular cascade
that results in dendritic spine formation.
leader Akira Sawa, M.D., Ph.D., professor of psychiatry and
director of the program in molecular psychiatry at the Johns
Hopkins University School of Medicine, says it is becoming
clear that having a defective DISC1 gene might lead to an
abnormally small number and size of dendritic spines, which
could lead nerve cells to maintain weaker connections with
unusually low numbers of neighboring neurons. Such abnormal
connectivity has long been seen in autopsied brains from schizophrenia
between neurons are constantly being made and broken throughout
life, with a massive amount of broken connections, or 'pruning,'
happening in adolescence," Sawa says. "If this pruning doesn't
happen correctly, it may be one reason for the pathogenesis
of schizophrenia," he adds.
second study, published in the Feb. 25 issue of Neuron,
Sawa's team generated a new animal model of schizophrenia
by temporarily shutting off the DISC1 gene in mice in the
prefrontal cortex, a brain area known to differ in schizophrenic
people. The new model allowed them to study other roles for
DISC1 in the brain.
created their novel model by, again, using RNA interference.
They injected short pieces of the nucleic acid RNA engineered
to shut off the DISC1 gene into cavities in the developing
brains of mouse fetuses two weeks after conception. Tests
showed that these snippets of RNA migrated into cells in the
prefrontal cortex, part of the brain located near the forehead.
was temporary, with the gene's function fully restored within
three weeks, or about a couple of weeks after birth. At various
times after the gene was reactivated, the scientists examined
the animals' brains and behavior, looking for differences
from normal mice.
team found that in the DISC1 shutoff group, nerve cells in
the prefrontal cortex that produce dopamine, one of the chemical
signals that nerve cells use to communicate, were markedly
immature as the animals entered adolescence. Furthermore,
the animals showed signs of a deficit of interneurons, nerve
cells that connect other neurons in neural pathways.
found several behavioral differences between these mice compared
to normal mice as the animals entered adolescence. For example,
those in the shutoff group reacted more strongly to stimulants,
displaying more locomotion than normal mice. Interestingly,
these effects were somewhat mitigated when the researchers
gave the animals clozapine, a drug used to treat schizophrenia.
together, Sawa says, results of both studies suggest that
these anatomical differences, which seem to be influenced
by the DISC1 gene, cause problems that start before birth
but surface only in young adulthood.
can learn more about the cascade of events that lead to these
anatomical differences, we may eventually be able to alter
the course of schizophrenia. During adolescence, we may be
able to intervene to prevent or lessen symptoms," Sawa says.
Johns Hopkins researchers who participated in the Nature
Neuroscience study include Akiko Hayashi-Takagi, Manabu
Takaki, Saurav Seshadri, Yuichi Makino, Anupamaa J. Seshadri,
Koko Ishizuka, Jay M. Baraban, and Atsushi Kamiya. Other Johns
Hopkins researchers who participated in the Neuron study
include Minae Niwa, Atsushi Kamiya, Hanna Jaaro-Peled, Saurav
Seshadri, Hideki Hiyama, and Beverly Huang.
Johns Hopkins Medical
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