(Press-News.org) Gene mutations that cause cell signaling networks to go awry during embryonic development and lead to major birth defects may also cause subtle disruptions in the brain that contribute to psychiatric disorders such as schizophrenia, autism, and bipolar disorder, according to new research by UC San Francisco scientists.
Over the past several years, researchers in the laboratory of psychiatrist Benjamin Cheyette, MD, PhD, have shown that mice with mutations in a gene called Dact1 are born with a range of severe malformations, including some reminiscent of spina bifida in humans.
In a new study designed to explore whether Dact1 mutations exert more nuanced effects in the brain that may lead to mental illness, Cheyette, John Rubenstein, MD, PhD, and colleagues in UCSF's Nina Ireland Laboratory of Developmental Neurobiology used a genetic technique in mice to selectively delete the Dact1 protein only in interneurons, a group of brain cells that regulates activity in the cerebral cortex, including cognitive and sensory processes. Poor function of interneurons has been implicated in a range of psychiatric conditions.
As reported in the June 24, 2013 online issue of PLOS ONE, when the research team examined these genetically altered interneurons in adult mice, they found that the cells appeared relatively normal and had managed to find their proper position in the brain's circuitry during development. But the cells had significantly fewer synapses, the sites where communication with neighboring neurons takes place. In additional observations not included in the new paper, the team also noted that the cells' dendrites, fine extensions that normally form bushy arbors studded with synapses, were poorly developed and sparsely branched.
"When you delete this gene function after initial, early development -- just eliminating it in neurons after they've formed -- they migrate to the right place and their numbers are correct, but their morphology is a little off," Cheyette said. "And that's very much in line with the kinds of pathology that people have been able to identify in psychiatric illness. Neurological illnesses tend to be focal, with lesions that you can identify or pathology you can see on an imaging study. Psychiatric illnesses? Not so much. The differences are really subtle and hard to see."
The Dact1 protein is part of a fundamental biological system known as the Wnt (pronounced "wint") signaling pathway. Interactions among proteins in the Wnt pathway orchestrate many processes essential to life in animals as diverse as fruit flies, mice, and humans, including the proper development of the immensely complex human nervous system from a single fertilized egg cell.
One way the Wnt pathway manages this task is by maintaining the "polarity" of cells during development, said Cheyette, "a process of sequestering, increasing the concentration of one set of proteins on one side of the cell and a different set of proteins on the other side of the cell." Polarity is particularly important as precursor cells transform into nerve cells, Cheyette said, because neurons are "the most polarized cells in the body," with specialized input and output zones that must wind up in the proper spots if the cells are to function normally.
Cheyette said his group is now conducting behavioral experiments with the mice analyzed in the new PLOS ONE paper and with genetically related mouse lines to test whether these mice have behavioral abnormalities in sociability, sensory perception, anxiety, or motivation that resemble symptoms in major psychiatric disorders. He also hopes to collaborate with UCSF colleagues on follow-up experiments to determine whether the activity of neurons lacking Dact1 is impaired in addition to the structural flaws identified in the new study and prior published work from his lab.
Meanwhile, as yet unpublished findings from human genetics research conducted by Cheyette's group suggest that individuals with autism are significantly more likely than healthy comparison subjects to carry mutations in a Wnt pathway gene called WNT1.
"Just because a gene plays an important role in the embryo doesn't mean it isn't also important in the brain later, and might be involved in psychiatric pathology," said Cheyette. "When these genes are mutated, someone may look fine, develop fine, and have no obvious medical problems at birth, but they may also develop autism in childhood or have a psychotic break in adulthood and develop schizophrenia."
Rubenstein is the Nina Ireland Distinguished Professor in Child Psychiatry.
###
Additional study authors include postdoctoral scholars Xiaoyong Yang, PhD, Daniel Vogt, PhD, and Amelia Stanco, PhD, and graduate student and first author Annie Arguello. Yang and Stanco are supported by a postdoctoral training grant (T32) led by Judy Ford, PhD, to the UCSF Department of Psychiatry from the National Institute of Mental Health.
Arguello conducted this research while obtaining her PhD in the UCSF doctoral program in Biomedical Sciences (BMS), and was supported by the Initiative to Maximize Student Development Program of the National Institute of General Medicine, as well as by BMS, the UCSF Department of Psychiatry, and the Center for Neurobiology and Psychiatry led by Sam Barondes, MD, Jeanne and Sanford Robertson Endowed Chair in Neurobiology and Psychiatry.
UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.
Follow UCSF
UCSF.edu | Facebook.com/ucsf | Twitter.com/ucsf | YouTube.com/ucsf
Genes involved in birth defects may also lead to mental illness
2013-06-25
ELSE PRESS RELEASES FROM THIS DATE:
700 women with urinary cancers missing out on prompt diagnosis every year
2013-06-25
This may be because family doctors tend to attribute women's - rather than men's - initial symptoms to harmless causes, such as bacterial infections, and some women therefore have to visit their GP several times before they get referred to a specialist, say the researchers.
Currently, survival rates for kidney and bladder cancer in England show that fewer women than men live for five years after diagnosis.
The researchers looked at the numbers of patients diagnosed with kidney and bladder cancers in England between 2009 and 2010. They used data from the National Audit ...
Breastfeeding boosts ability to climb social ladder
2013-06-25
The findings are based on changes in the social class of two groups of individuals born in 1958 (17,419 people) and in 1970 (16,771 people).
The researchers asked each of the children's mums, when their child was five or seven years old, whether they had breastfed him/her.
They then compared people's social class as children - based on the social class of their father when they were 10 or 11 - with their social class as adults, measured when they were 33 or 34.
Social class was categorised on a four-point scale ranging from unskilled/semi-skilled manual to professional/managerial. ...
Study sets guidelines for stem cell transplants in older patients with myelodysplastic syndromes
2013-06-25
BOSTON -- A new study by an international team led by Dana-Farber Cancer Institute scientists provides the first statistically-based guidelines for determining whether a stem cell transplant is appropriate for older patients with myelodysplastic syndromes (MDS) – the most common blood disorders in people over 60 years of age, and frequently a precursor for leukemia.
Using mathematical models to analyze hundreds of MDS cases from around the world, the researchers found reduced intensity transplants of donor stem cells are advisable for patients aged 60-70 who have higher-risk ...
NMR advance brings proteins into the open
2013-06-25
PROVIDENCE, R.I. [Brown University] —When working a cold case, smart investigators try something new. By taking a novel approach to nuclear magnetic resonance spectroscopy – a blending of four techniques – scientists have been able to resolve a key interaction between two proteins that could never be observed before. They report on their findings the week of June 24, 2013 in Proceedings of the National Academy of Sciences (PNAS).
The interaction the team became the first to describe is nearly universal across all of life. A protein machines called a chaperone takes hold ...
Stray gases found in water wells near shale gas sites
2013-06-25
DURHAM, NC -- Homeowners living within one kilometer of shale gas wells appear to be at higher risk of having their drinking water contaminated by stray gases, according to a new Duke University-led study.
Duke scientists analyzed 141 drinking water samples from private water wells across northeastern Pennsylvania's gas-rich Marcellus shale basin. Their study documented not only higher methane concentrations in drinking water within a kilometer of shale gas drilling -- which past studies have shown -- but higher ethane and propane concentrations as well.
Methane ...
Computer models shed new light on sickle cell crisis
2013-06-25
VIDEO:
Researchers from Brown University modeled the stickiness of cells associated with sickle cell anemia. The models suggest that squishy SS2 cells are more likely to get stuck to vessel walls...
Click here for more information.
PROVIDENCE, R.I. [Brown University] — Using powerful computer models, researchers from Brown University have shown for the first time how different types of red blood cells interact to cause sickle cell crisis, a dangerous blockage of blood flow in capillaries ...
Study examines benefits, risks to cognitive function of HRT for women ages 50 to 55 years
2013-06-25
Postmenopausal hormone therapy with conjugated equine estrogens (CEEs) was not associated with overall sustained benefit or risk to cognitive function when given to women ages 50 to 55 years, according to a report published Online First by JAMA Internal Medicine, a JAMA Network publication.
The Women's Health Initiative Memory Study (WHIMS) demonstrated that postmenopausal hormone therapy with CEEs, when prescribed to women 65 years and older, caused deficits in global and domain-specific cognitive functioning.
The Women's Health Initiative Memory Study of Younger Women ...
Hospital mortality rates may be linked to performance on publicly reported medical conditions
2013-06-25
Hospital performance on publicly reported conditions (acute myocardial infarction [heart attack], congestive heart failure, and pneumonia), may potentially be used as a signal of overall hospital mortality rates, according to a study by Marta L. McCrum, M.D., of Harvard School of Public Health, Boston, and colleagues. (Online First)
Using national Medicare data from 2,322 acute care hospitals, the authors examined whether mortality -rates for publicly reported medical conditions are correlated with hospitals' overall performance. The sample included 6,670,859 hospitalizations ...
Conversations with teens about weight linked with increased risk of unhealthy eating behaviors
2013-06-25
Conversations between parents and adolescents that focus on weight and size are associated with an increased risk for unhealthy adolescent weight-control behaviors, according to a study published Online First by JAMA Pediatrics, a JAMA Network publication.
The study by University of Minnesota, Minneapolis, researchers also found that overweight or obese adolescents whose mothers engaged in conversations that were focused only on healthful eating behaviors were less likely to diet and use unhealthy weight-control behaviors (UWCBs).
"Because adolescence is a time when ...
Risk of death from ischemic stroke appears to have decreased in US black children
2013-06-25
The excess risk of death from ischemic (due to reduced blood flow), but not hemorrhagic (due to bleeding), stroke in US black children has decreased over the past decade, according to a study by Laura L. Lehman, M.D., of Boston Children's Hospital, and colleagues. (Online First)
The study analyzed death certificate data from the National Center for Health Statistics for all children who died from 1988 through 2007 in the United States. Among 1.6 billion person-years of US children (1988-2007), there were 4,425 deaths attributed to stroke, yielding an average of 221 deaths ...