How would a schizophrenic mouse behave?
It would hear voices, and experience paranoid delusions, like many humans
with the disorsder. It would become apathetic, have trouble concentrating,
withdraw from other mice, and perhaps develop alogia, also known as poverty of
Producing a testable mouse that displays the conspicuous symptoms
of such a distinctly human disease seems impossible, especially since the
disease manifests itself primarily through the uniquely human capacities for
language and imagination. Without a reliable animal model, however, the search
for drug treatments will lag, and any insights into the brain malfunctions that
produce the symptoms of schizophrenia will depend on the study of human
patients, whose brains are usually physically and morally off-limits.
mice don't get Alzheimer's disease or Parkinson's disease either, and useful
mouse models of those diseases exist. Or rather, mouse models exist for various
aspects of those diseases. Why couldn't schizophrenia be broken into components,
with each one modeled by a separate strain of mouse?
what researchers at trying to do. A mouse has been bred at Johns Hopkins
University in Baltimore, for example, that lacks the enzyme BACE1, which
contributes to the accumulation of protein fragments believed to damage neurons
in Alzheimer's disease. However, these mice also become hyperactive when placed
in an unfamiliar situation-a behavior reminiscent of the agitation of people in
the grip of schizophrenia. The mice also continue to startle in response to a
loud noise or bright flash even when alerted by a warning signal, which normally
quells the startle reflex-except in people with schizophrenia, Alzheimer's
disease, and a few other disorders. In addition, the mice appear to lack
interest in new mice, and they show deficits in working memory-two more
behaviors that resemble symptoms of schizophrenia. The clincher? All of these
behaviors improve when the mice are given clozapine, a common antipsychotic
Why would a mouse created to help researchers find treatments for
Alzheimer's disease seem to display symptoms of schizophrenia?
Researchers found that BACE1, in addition to producing the protein fragments
believed to initiate Alzheimer's, also plays a role in the pathway for
neuregulin1, a protein implicated in schizophrenia. (It appears to disrupt the
formation of dendritic spines on neurons.)
"When we discovered that BACE1
plays a role in the so-called neuregulin pathway, we started to look at the
BACE1 knockout mice as a possible model of schizophrenia," said Alena V.
Savonenko, an associate professor at the Johns Hopkins University School of
Medicine, and the lead author of a paper on the subject published
in PNAS in 2009. (please see full citation below, 1)
recognize the limitations of this model of schizophrenia. "No animal model could
encompass the complexity of this human disease, so you must try to interpret
what part of the symptoms this model represents," she said. "Only by having a
number of models, each providing information about one particular mechanism
behind the symptoms, could you ever develop a complete model of the
Since schizophrenia runs in families, researchers hope to
create strains of mice engineered to carry human genes suspected of contributing
to symptoms. This type of genetic engineering has become commonplace. The only
problem is that schizophrenia appears to be caused by contributions from dozens
and possibly hundreds of genes.
Joshua Gordon, a psychiatry professor at
Columbia University, focuses on one of them-22q11, a gene regarded as one of the
largest genetic risk factors for schizophrenia. A microdeletion in the gene
increases the risk of schizophrenia 30 times. Two of his collaborators, Maria
Karayiorgou, of the New York State Psychiatric Institute, and Joseph A. Gogos,
of Columbia University, developed a mouse model of schizophrenia by knocking out
22q11. When they studied the mice they observed deficits in working memory and
other cognitive functions; this work was published
in Nature in 2010.(2)
"By deleting 22q11, the connections
between the hippocampus and the prefrontal cortex of the mouse are disrupted,"
Gordon said. "With genes, I know I'm studying a causative agent, and I can test
my hypothesis that the 22q11 gene causes cognitive symptoms in schizophrenia by
interfering with the hippocampal prefrontal system."
Lin Mei, director of
the Institute of Molecular Medicine and Genetics at Georgia Regents University
in Augusta, has made mouse models lacking genes for ErbB4 and neuregulin-1,
which work together to balance inhibition and excitation in pyramidal cells in
the prefrontal cortex; some of this work was published
in PNAS in 2009. (3)
"Because of the Human Genome Project, some
susceptibility genes associated with schizophrenia have been identified, and
they gave us a handle on how schizophrenia may work," Mei said. "Neuregulin and
ErbB4 are both susceptibility genes, so we generated mouse models of each and
found behavioral deficits in them."
Some of the mice appear to be
hyperactive, for example, and run around furiously for no apparent reason. Some
continue to jump when startled, despite a warning signal that alerts them to the
approaching stimulus. Others have problems with working memory.
very excited by this," Mei said, "but we have a long way to go to understand
such complex behavior."
Mei suspects that schizophrenia, like autism,
exists on a broad spectrum, with symptoms varying widely from person to person.
"I predict that in 50 years schizophrenia will be grouped into 20 or even 50
different diseases, each one caused by a different combination of mechanisms,"
he said. "Neuregulin and ErbB4 may account for no more than 2 percent of cases.
There's no way for us to create a model that would duplicate every single
symptom in schizophrenic patients, but we hope we can create models piece by
piece to tease out the mechanism of schizophrenia."
That means piecing
together a multitude of tiny clues until a clear picture of schizophrenia begins
to emerge-an arduous and perhaps futile task in the opinion of Peter C.
Williamson, chair of neuroscience and mental health at the University of Western
Ontario's Schulich School of Medicine.
"People have done some very clever
things to mimic aspects of schizophrenia," he said. "I think it's possible to
model some aspects of the illness, but not the illness itself."
Williamson is the co-author, with John C. Allman of the California Institute
of Technology, of The
Human Illnesses: Neuropsychiatric Disorders and the Nature of the Human
Brain. They contend that neuropsychiatric disorders such as
schizophrenia, bipolar disorder, autism, and others, result from the malfunction
of characteristics unique to the human brain.
"These are human
disorders," they state in the preface. "If we could understand more about what
makes the human brain unique, then maybe we might understand how it breaks down,
resulting in these conditions. The brain breaks down in discrete ways, and how
it breaks down tells us something about how it was put together." (4)
Williamson considers some of the mouse models potentially useful, but he
still catches himself asking, "Is this really relevant to schizophrenia?"
His answer? "Probably not. I think schizophrenia, and probably bipolar
disorder and autism as well, are uniquely human disorders. They affect circuits
present only in humans. They depend on higher cortical networks that have
developed only in humans."
In their book Williamson and Allman contend
that the human illnesses depend heavily on the uniquely human ability to think
about the thoughts, feelings, and actions of the self and others.
animals really don't do that," Williamson said. "Our brain is designed to do
that, and several regions have evolved to enable us to do that. The disorders we
have probably arise from this capacity. That's why when I look at people trying
to develop a mouse model of schizophrenia, I think, good luck."
of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in
BACE1-null mice. Savonenko AV, Melnikova T, Laird FM, Stewart KA, Price DL,
Wong PC. PNAS 2009;105(14):5585-5590.
hippocampal-prefrontal synchrony in a genetic mouse model of schizophrenia.
Torfi Sigurdsson, Kimberly L. Stark, Maria Karayiorgou, Joseph A. Gogos, and
Joshua A. Gordon. Nature 2010;464(7289):763-767.
1 regulates pyramidal neuron activity via ErbB4 in parvalbumin-positive
interneurons. Lei Wen et al. PNAS 2010;107(3):12111-1216.
The Human Illnesses: Neuropsychiatric Disorders and the Nature of the Human
Brain, by Peter C. Williamson and John M. Allman. Oxford University Press