Gene-Environment Interactions Could Influence Several Psychiatric Disorders; 'Schizophrenia Gene' May Also Trigger Anxiety, Depression

A December 3rd media release from Johns Hopkins University:

BALTIMORE, Dec. 3 (AScribe Newswire) -- Male mice born with a genetic mutation that's believed to make humans more susceptible to schizophrenia develop behaviors that mimic other major psychiatric illnesses when their mothers are exposed to an assault to the immune system while pregnant, according to new Johns Hopkins research.

What was most surprising to researchers was that the mental illnesses the mice developed didn't look like schizophrenia, which they were genetically predisposed to, but more like mood and anxiety disorders, suggesting that one gene mutation can lead to different mental illnesses when influenced by the same environmental factor.

"Psychiatric diseases have genetic roots, but genes alone do not explain the entire disease," says Mikhail V. Pletnikov, M.D., Ph.D. [pictured], an associate professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine and the study's leader. "When we study genes in conjunction with environmental challenges, we can better understand how diseases develop."

Pletnikov hopes his research, which appears in the December issue of the journal Biological Psychiatry, may be a small step toward eventually finding ways to prevent mental illnesses in humans. "The main goal here is to understand how gene-environment interactions take place on the molecular level so that you can find suitable drug targets, ultimately stopping these diseases before they happen," he says. "It all can start before birth."

Pletnikov and his team studied a mutant human form of the Disrupted-in-Schizophrenia 1 gene (mhDISC1), breeding mice in the laboratory with this mutation. This genetic variation is believed to be associated with vulnerability to major mental illnesses in humans. The mhDISC1 mice were impregnated, and at the ninth day of gestation (the equivalent to the middle or end of the first trimester in a human pregnancy), one group was given a drug to stimulate the immune system, forcing it to react as if it had been exposed to a virus like influenza or a parasite like toxoplasma. The rest of the pregnant mice - whose fetuses also had the mutated gene- were kept as a control group and their immune systems were left unchallenged.

The study found that prenatal immune stimulation in mhDISC1 mice produced behavioral abnormalities that were not present in the unchallenged mice: elevated anxiety, depression-like responses, an altered pattern of sociability and a weakened response to stress. The unchallenged mice did not show those behaviors, even though they also had the mutant gene. Pletnikov says the findings suggest that the same mutation, in this case mhDISC1, can lead to different illnesses, depending on interactions with environmental factors.

This may provide an explanation, he says, for why the extended Scottish family in which scientists first discovered this genetic mutation had members who suffered not solely from schizophrenia but also from major depression and bipolar disorder. "This one gene mutation can lead to very different clinical manifestations," Pletnikov says.

Along with the behavior differences, Pletnikov and his team also found that parts of the brain, including the amygdala and the hypothalamus, were smaller in the mice that had been prenatally challenged. A similar abnormality can be found in those same areas of the brain in humans with major depression and bipolar disorder.

Previous studies have suggested that the prenatal immune response to a microbe - be it a major illness or just transient flu-like symptoms barely noticed by the pregnant woman - may be responsible for the increased incidence of adult psychopathology in humans. But this hypothesis, Pletnikov says, has been difficult to prove. Using this mouse model, he suggests, is a valuable way to study the relationship between gene-environment interactions and mental illness, and should be replicated to find more of these interactions to gain a better understanding of these relationships.

Future studies, he says, will try to sort out whether different timing or stimulating different parts of the immune system might lead to specific types of mental illness, as well as explore the consequences of other environmental adverse events such as stress or drug abuse.

Other Johns Hopkins researchers on the study include Bagrat Abazyan, M.D.; Jun Nomura, Ph.D.; Geetha Kannan; Koko Ishizuka, Ph.D.; Kellie L. Tamashiro, Ph.D.; Frederick Nucifora, Ph.D.; Vladimir Pogorelov, Ph.D.; Chunxia Yang; Carlos Pardo, M.D.; Susumu Mori, Ph.D.; Atsushi Kamiya, M.D., Ph.D.; Akira Sawa, M.D., Ph.D.; and Christopher A. Ross, M.D., Ph.D.

The study was supported by the National Institute of Mental Health, Autism Speaks, the National Alliance for Research on Schizophrenia and Depression, the Mortimer W. Sackler Foundation, the Cell Science Research Foundation and the National Institutes of Health/National Institute on Drug Abuse-Intramural Research Program.

For more information: http://www.hopkinsmedicine.org/psychiatry/research/neurobiology/research_labs/behavioral_pletnikov.html

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CONTACT: Stephanie Desmon, Johns Hopkins Medicine Media Relations and Public Affairs, 410-955-8665, sdesmon1@jhmi.edu

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Gene 'has key schizophrenia role'

An article posted today by BBC News:

Two studies have pinpointed a single gene as key to the development and treatment of schizophrenia.

A US team from the Howard Hughes Medical Institute found that a mutated version of the DISC1 gene disrupts the growth and development of brain cells.

And a team from the University of Edinburgh showed that the gene affects how patients respond to treatment.

Both studies, published in the journals PLoS One and Cell, raise hopes of more effective treatment for schizophrenia.

To read the entire article, please click here.

Also see:

Disrupted in Schizophrenia 1 Regulates Neuronal Progenitor Proliferation via Modulation of GSK3(beta)/beta-Catenin Signaling

The DISC1 Pathway Modulates Expression of Neurodevelopmental, Synaptogenic and Sensory Perception Genes

I thank John Devlin and Dr. Roger Cann for bringing this article to my attention.

Hopkins Researchers Piece Together Gene "Network" Linked to Schizophrenia

--Patients Confirmed to Carry Mutations

A September 2nd press release from Johns Hopkins Medicine, Media Relations and Public Affairs:

Reporting this week in the Archives of General Psychiatry, researchers at the Johns Hopkins University School of Medicine have uncovered for the first time molecular circuitry associated with schizophrenia that links three previously known, yet unrelated proteins.

"This is very exciting because until now the many known genetic factors implicated in this condition were not connected in any way," says Akira Sawa, M.D., Ph.D., director of the program in molecular psychiatry and associate professor of psychiatry and neuroscience at Hopkins. "Now, through a cross-disciplinary and cross-departmental collaboration, we not only have figured out how these three proteins interact with each other, we also have found patients who carry mutations. These results give us a really good foundation to dig deeper into such an elusive condition."

Sawa's team previously had characterized the DISC1 gene and protein which are required for proper nervous system development, and when disrupted, significantly contribute to schizophrenia. His team also had shown that DISC1 protein binds to PCM1 protein at the centrosome, which coordinates the structure and movement of cells.

Separately, Hopkins geneticist and associate professor of ophthalmology Nicholas Katsanis, Ph.D., and his team were studying an unrelated family of proteins had discovered that one of them, BBS4, also is found near the centrosome and also binds to PCM1. "But we weren't thinking schizophrenia at the time because BBS4 is involved in Bardet-Biedl Syndrome, which is a wide-ranging condition mainly known for its associated eye and and kidney problems but also does cause behavioral defects in some patients," says Katsanis.

It was Hopkins psychiatrist Nicola Cascella, M.D., co-director of the program in molecular psychiatry and assistant professor of psychiatry who, according to Sawa, "brought it all together" by realizing that the behavioral defects seen in Bardet-Biedl Syndrome patients and the molecular interaction of BBS4 and PCM1 could be related and relevant to schizophrenia.

"Serendipity brought us together from the far corners of campus and allowed us to see the links between these three proteins, centrosomes, and schizophrenia," says Katsanis. So they embarked on a collaboration to see if these coincidental observations would lead to a better understanding of schizophrenia.

First, to show that the three proteins do in fact physically interact with each other in a cell, the research teams attached different tags to each protein and followed the proteins in cells grown in the lab. They found that all three proteins do end up together, at the centrosome. When the researchers removed either DISC1 or BBS4 from cells, PCM1 would not make it to the centrosome, leading the researchers to conclude that DISC1 and BBS4 act together to recruit PCM1.

The researchers then asked if the failure of PCM1 recruitment to the centrosome in mice lacking either DISC1 or BBS4 affects brain development. To do this they reduced the amount of each of the three factors in the brains of developing mice. As a result, nerve cells in the cerebral cortex-the part of the brain responsible for memory and thought-failed to grow properly, suggesting that these three proteins act together synergistically during normal brain development.

The teams' next question was whether PCM1 could contribute to schizophrenia. By examining DNA from families with schizophrenia, the researchers discovered a mutation in PCM1 in one family, but only carried by family members who had been diagnosed with schizophrenia.

"This connection is exactly the sort of daisy chain from gene to disease that psychiatrists pray for," says Cascella. "This is a molecular pathway that we can potentially target for drug therapy."

"We are beginning to sub-stratify psychiatric illness into discrete molecular causes," adds Katsanis. "Now that we know that that a subset of schizophrenia is related to centrosomes and these associated proteins, we can start looking at broader questions of how people get psychiatric illness. We have a hook, now we can start fishing."

The research was funded by the National Institutes of Mental Health Silvio O. Conte Center grant, U.S. Public Health Service, as well as foundation grants from Stanley, NARSAD, and S-R. It was also funded by the Japanese ministry and foundations of JSPS, Japan Brain, Tokyo Biochemical Research and Brain Science

Authors on the paper are Atushi Kamiya, Perciliz Tan, Caitlin Englehard, Koko Ishizuka, Pulver, Cascella, Katsanis, and Sawa, all of Hopkins; Ken-ichiro Kubo and Kazunori Nakajima of Keio University in Tokyo, Japan; and Akiharu Kubo and Sachiko Tsukita of Kyoto University in Kyoto, Japan.

Also see:

Recruitment of PCM1 to the Centrosome by the Cooperative Action of DISC1 and BBS4: A Candidate for Psychiatric Illnesses (PDF)

New schizophrenia pathway discovered by chance

Mouse model for schizophrenia has genetic on-off switch

A September 10th news release from Johns Hopkins Medicine:

Scientists at Johns Hopkins have developed a mouse model for schizophrenia in which a mutated gene linked to schizophrenia can be turned on or off at will.

The researchers developed the transgenic mouse by inserting the gene for mutant Disrupted-In-Schizophrenia-1 (DISC-1) into a normal mouse, along with a promoter that enables the gene to be switched on or off. Mutant DISC-1 was previously identified in a Scottish family with a strong history of schizophrenia and related mental disorders.

The study was performed in the laboratory of Mikhail Pletnikov, M.D., Ph.D., in the Department of Psychiatry and Behavioral Sciences.

Last month, another Hopkins researcher in the Department of Psychiatry and Behavioral Sciences, Akira Sawa, M.D., Ph.D., and his team, developed a comparable mutant DISC-1 mouse model for schizophrenia. Pletnikov’s is the first model in which researchers can control the expression of this mutated gene, and the model illuminates additional aspects of the biology of the disorder.

Researchers turn off the mutant DISC-1 gene by feeding the mice a nontoxic chemical that controls a genetically engineered switch mechanism to turn on production of the DISC-1 protein.

The study, which appears in the September issue of Molecular Psychiatry, showed that male mice with the mutant DISC-1 gene were significantly more active than control mice without the mutated gene. The investigators also observed that the male mutant DISC-1 mice had altered social interactions with other mice and were more aggressive. Females with the mutated gene had a more difficult time remembering how to navigate a maze.

“Schizophrenia is a human disorder, so we cannot say the symptoms displayed by the mouse model are schizophrenic. But they are in line with the kinds of behavioral changes we see in humans with schizophrenia,” says Pletnikov.

The research showed other strong similarities between the mouse model and humans with schizophrenia.

Examination of the brains of the mutated mice using MRI scans showed significant enlargement of the lateral ventricles (fluid-filled areas in the front of the brain), very similar to MRI findings in humans with schizophrenia.

Tissue culture studies showed that there was an abnormality in the development of brain cells in the part of the brain generally associated with schizophrenia. Also, the transgenic mice had abnormal levels of the proteins 25 kDa synaptosome-associated protein (SNAP-25) and lissencephaly-1 (LIS-1).

It’s known from previous research that SNAP 25 and LIS-1 are key players in brain cell development and maturation, and several prior studies of brain tissue from humans with schizophrenia showed abnormal levels of SNAP-25.

“This model supports the idea that schizophrenia is a disease associated with abnormal brain development,” says senior co-author of the study Christopher Ross, M.D., Ph.D., of the Department of Psychiatry and Behavioral Sciences. “And being able to regulate the timing of expression of the mutant protein provides an opportunity to study the timing and mechanism of specific abnormalities -- a tool that could eventually lead to the discovery of drugs that could potentially control or even prevent the disease.”

Additional authors of the study from Johns Hopkins include Yavuz Ayhan, M.D., Olga Nikolskaia, M.D., Yanqun Xu, M.S., and Timothy H. Moran, Ph.D., of the Department of Psychiatry and Behavioral Sciences; and Hao Huang, Ph.D., and Susumu Mori, Ph.D., of the Department of Radiology-Magnetic Resonance Research.

This study was supported by the Stanley Medical Research Institute, a NARSAD Distinguished Investigator Award, the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke.

Normal Role for Schizophrenia Risk Gene Identified

A September 7th press release from Johns Hopkins Medicine:

--disc1 makes protein that helps new neurons integrate into our neural network

How the gene that has been pegged as a major risk factor for schizophrenia and other mood disorders that affect millions of Americans contributes to these diseases remains unclear. However, the results of a new study by Hopkins researchers and their colleagues, appearing in Cell this week, provide a big clue by showing what this gene does in normal adult brains.

It turns out that this gene, called disc1, makes a protein that serves as a sort of musical conductor for newly made nerve cells in the adult brain, guiding them to their proper locations at the appropriate tempo so they can seamlessly integrate into our complex and intertwined nervous system. If the DISC1 protein doesn’t operate properly, the new nerves go hyper.

"DISC1 plays a broader role in the development of adult nerves than we anticipated," says Hongjun Song, Ph.D., an associate professor at Hopkins’ Institute for Cell Engineering. "Some previous studies hinted that DISC1 is important for nerve migration and extension, but our study in mice suggests it is critical for more than that and may highlight why DISC1 is associated with multiple psychiatric disorders."

"Almost every part of the nerve integration process speeds up," adds fellow author Guo-li Ming, M.D., Ph.D., also an associate professor at ICE. "The new nerves migrate and branch out faster than normal, form connections with neighbors more rapidly, and are even more sensitive to electrical stimulation."

While it may not be obvious why high-speed integration would be detrimental, Song notes that because of the complexity of the brain, timing is critical to ensure that new nerves are prepared to plug into the neural network.

Ming, Song and their collaborators at the National Institutes of Health and UC Davis tracked the abnormal movements of the hyperactive nerve cells by injecting a specially designed virus into a part of a mouse brain known as the hippocampus -a region important for learning and memory and therefore quite relevant to psychiatric disorders. The virus would only infect newly born cells and would both knock down the expression of the disc1 gene and make the nerves glow under a microscope.

Combined with other recent Hopkins research that successfully engineered mouse models that have abnormal DISC1 and can effectively reproduce schizophrenia symptoms such as anxiety, hyperactivity, apathy and altered senses, these current findings teasing out the normal role of this protein may help unravel the causes for this complex disease

Song and Ming add that their studies in the hippocampus - one of the few places where new nerves are made in the adult brain - might answer why symptoms typically first appear in adults despite the genetic basis of many psychiatric illnesses. They plan on continuing their mouse work to try and find those answers.

The research was funded by the National Institutes of Health, McKnight Scholar Award, Whitehall Foundation and a Klingenstein Fellowship Award in the Neurosciences

Authors on the paper are Jay Chang, Sundar Ganesan & Bai Lu of the National Institutes of Mental Health; Regina Faulkner, Xiao-bo Liu & Hwai-Jong Cheng of the University of California, Davis; and Xin Duan, Shaoyu Ge, Ju Young Kim, Yasuji Kitabatake, Chih-Hao Yang, J. Dedrick Jordan, Dengke Ma, Cindy Liu, Guo-li Ming and Hongjun Song of Hopkins.

On the Web:

www.hopkins-ice.org/neuro/int/song.html

www.cell.org

Click here for more information from the Schizophrenia Research Forum.

Researchers may have schizophrenia breakthrough

From CTV.ca (May 3, 2007):

A team of Canadian and Scottish scientists has pinpointed one of the genes that causes schizophrenia -- a breakthrough that sheds new light on how the disease can develop.

The work is to be published Thursday [May 3rd] in the journal Neuron [to view the abstract, click here].

It demonstrates for the first time that schizophrenia can be caused by a malfunctioning gene, suggesting schizophrenia is linked to depression and bipolar disorder and may have the same underlying cause.

The discovery may someday help doctors identify which patients will respond to different types of treatments.

Click on the arrow to start the video.

Many thanks to Charlie G. for help with this posting.