Genes involved in birth defects may also lead to mental illness

June 24, 2013, University of California, San Francisco

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 used a genetic technique in mice to selectively delete the Dact1 protein only in interneurons, a group of that regulates activity in the , including cognitive and sensory processes. Poor function of interneurons has been implicated in a range of .

As reported in the June 24, 2013 online issue of PLOS ONE, when the research team examined these genetically altered interneurons in , 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 , 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 . He also hopes to collaborate with UCSF colleagues on follow-up experiments to determine whether the activity of 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.

Explore further: Defects in brain cell migration linked to mental retardation

Related Stories

Defects in brain cell migration linked to mental retardation

June 21, 2013
(Medical Xpress)—A rare, inherited form of mental retardation has led scientists at Washington University School of Medicine in St. Louis to three important "travel agents" at work in the developing brain.

Human brain cells developed in lab, grow in mice

May 8, 2013
A key type of human brain cell developed in the laboratory grows seamlessly when transplanted into the brains of mice, UC San Francisco researchers have discovered, raising hope that these cells might one day be used to treat ...

Unraveling how a mutation can lead to psychiatric illness

November 17, 2011
In recent years, scientists have discovered several genetic mutations associated with greater risk of psychiatric diseases such as schizophrenia and bipolar disorder. One such mutation, known as DISC1 — an abbreviation ...

Protein identified that can disrupt embryonic brain development and neuron migration

January 14, 2013
Interneurons – nerve cells that function as 'dimmers' – play an important role in the brain. Their formation and migration to the cerebral cortex during the embryonic stage of development is crucial to normal brain functioning. ...

Scientists discover key signaling pathway that makes young neurons connect

June 20, 2013
Neuroscientists at The Scripps Research Institute (TSRI) have filled in a significant gap in the scientific understanding of how neurons mature, pointing to a better understanding of some developmental brain disorders.

Turning human stem cells into brain cells sheds light on neural development

May 2, 2013
Medical researchers have manipulated human stem cells into producing types of brain cells known to play important roles in neurodevelopmental disorders such as epilepsy, schizophrenia and autism. The new model cell system ...

Recommended for you

Short-course treatment for combat-related PTSD offers expedited path to recovery

January 23, 2018
Symptoms of Post-Traumatic Stress Disorder (PTSD) can be debilitating and standard treatment can take months, often leaving those affected unable to work or care for their families. But, a new study demonstrated that many ...

Curcumin improves memory and mood, study says

January 23, 2018
Lovers of Indian food, give yourselves a second helping: Daily consumption of a certain form of curcumin—the substance that gives Indian curry its bright color—improved memory and mood in people with mild, age-related ...

Priming can negate stressful aspects of negative sporting environments, study finds

January 23, 2018
The scene is ubiquitous in sports: A coach yells at players, creating an environment where winning is the sole focus and mistakes are punished. New research from the University of Kansas shows that when participants find ...

Social and emotional skills linked to better student learning

January 23, 2018
Students with well-developed and adaptive social and emotional behaviours are most likely to excel in school, according to UNSW researchers in educational psychology.

People with prosthetic arms less affected by common illusion

January 22, 2018
People with prosthetic arms or hands do not experience the "size-weight illusion" as strongly as other people, new research shows.

Intensive behavior therapy no better than conventional support in treating teenagers with antisocial behavior

January 19, 2018
Research led by UCL has found that intensive and costly multisystemic therapy is no better than conventional therapy in treating teenagers with moderate to severe antisocial behaviour.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.