A mouse model that mirrors schizophrenia-like traits would go a long way to
help researchers explore the causes and test cures for the disease. So far,
the nearest scientists have gotten is dosing rodents with amphetamine or
phencyclidine to mimic behavior typical of schizophrenia.
A team led by Johns Hopkins researchers, however, has now developed the
first transgenic mouse with a mutated gene that produces both behavioral and
anatomical deficits similar to those associated with schizophrenia in
"We have produced a significant, if subtle, change in phenotype that
can be used to test other factors or serve as a drug screen," said Akira
Sawa, M.D., Ph.D., an associate professor of psychiatry and neuroscience and
director of the program in molecular psychiatry at Hopkins, in an interview.
Sawa led the 15 researchers who developed the mouse.
Mouse models have been developed "extremely slowly," Douglas
Meinecke, Ph.D., program officer in the Clinical Neuroscience Research Branch
of the National Institute of Mental Health, told Psychiatric News.
Another eight or 10 mutant genes have been identified, and some have been
inserted into mice.
Schizophrenia is a heterogeneous disease with multiple symptoms and causes,
including genetic, said Meinecke.
Sawa and colleagues created two mouse lines with a dominant-negative
disrupted-in-schizophrenia (DN-DISC1) gene. Proteins expressed by DISC1 are
involved in dendritic outgrowth and development of the cerebral cortex.
Mutated versions of the gene have been tied to susceptibility for
schizophrenia, bipolar disorder, and major depression and correlated with
psychiatric disorders in an extended Scottish family, according to research
published in the September 4 Proceedings of the National Academy of
"So far we've seen a lot of weakly related gene studies with small
effects, including DISC1," he said. "Now we need to perturb the
gene and see what happens. What's wrong, why is it wrong, and how does it
work? The new mouse models may let us look at real potential mechanisms for
how the disease works."
Sawa's team found indications of anatomical changes in the transgenic mice.
Left-to-right asymmetry in the lateral ventricles found in unmutated mice was
lost or reversed in the DN-DISC1 mice. At 6 weeks of age, the lateral
ventricles in the brain were significantly enlarged, although that difference
disappeared at age 3 months.
"Enlarged ventricles are important biomarkers for schizophrenia, but
that is only one of several facets of the disorder and not diagnostic,"
The researchers could not explain the initial, temporary enlargement of the
Nevertheless, because schizophrenia usually develops between the ages of 18
and 24, changes in ventricle size at least imply some role for DISC1, said
Meinecke. "Simply the fact that the researchers found neurodevelopmental
differences at all is important," he said.
They also found deficits that underlie abnormal neural synchrony and
impaired sensorimotor gating, according to Sawa and colleagues.
"Consistent abnormalities of such [schizophrenia]-associated changes
can suggest that the present mouse model may mimic at least a subset of human
[schizophrenia]," the researchers wrote. "Our results indicate
that the enlargement of DISC1-DN is associated with deficits in
neurodevelopment, but not with the process of progressive
Behavioral tests found an increase in hyperactivity, especially late in the
trials, when ordinary mice should have gotten used to their surroundings.
Transgenic mice took longer to find food, possibly reflecting problems either
with their sense of smell or a lack of motivation. Tests for anxiety, motor
coordination, and spatial learning produced no differences.
A related study in the September 11 Molecular Psychiatry by Sawa's
co-author and Hopkins colleague, Mikhail Pletnikov, M.D., Ph.D., found that,
compared with controls, DISC1 transgenic male mice also displayed alterations
in social interaction, and transgenic female mice showed deficient spatial
memory, behavior similar to some features of schizophrenia.
Sawa and his colleagues will next use positron emission tomography to
visualize neural transmission and metabolism in the mice to help correlate the
animal model to effects in human tissue, he said. They will also collaborate
with other researchers, supplying mice to test how perinatal or prenatal
stressors (such as some infectious diseases like toxoplasmosis) may affect the
The research was supported by grants from the U.S. Public Health Service,
the Neurogenetics and Behavior Center at Johns Hopkins, the National Alliance
for Research on Schizophrenia and Depression, the Stanley Medical Research
Institute, and the S-R Foundation.
An abstract of "Dominant-Negative DISC1 Transgenic Mice
Display Schizophrenia-Associated Phenotypes Detected by Measures Translatable
to Humans" is posted at<www.pnas.org/cgi/content/abstract/0704774104v1>.▪