New brain connections form in clusters during learning

Researchers track structural changes during formation of new memories

SANTA CRUZ, CA--New connections between brain cells emerge in clusters in the brain as animals learn to perform a new task, according to a study published in Nature on February 19 (advance online publication). Led by researchers at the University of California, Santa Cruz, the study reveals details of how brain circuits are rewired during the formation of new motor memories ceus for social workers

The researchers studied mice as they learned new behaviors, such as reaching through a slot to get a seed. They observed changes in the motor cortex, the brain layer that controls muscle movements, during the learning process. Specifically, they followed the growth of new "dendritic spines," structures that form the connections (synapses) between nerve cells.

"For the first time we are able to observe the spatial distribution of new synapses related to the encoding of memory," said Yi Zuo, assistant professor of molecular, cell and developmental biology at UC Santa Cruz and corresponding author of the paper.

In a previous study, Zuo and others documented the rapid growth of new dendritic spines on pyramidal neurons in the motor cortex during the learning process. These spines form synapses where the pyramidal neurons receive input from other brain regions involved in motor memories and muscle movements. In the new study, first author Min Fu, a postdoctoral researcher in Zuo's lab, analyzed the spatial distribution of the newly formed synapses.

Initial results of the spatial analysis showed that one third of the newly formed synapses were located next to another new synapse. These clustered synapses tended to form over the course of a few days during the learning period, when the mouse was repeatedly performing the new behavior. Compared to non-clustered counterparts, the clustered synapses were more likely to persist through the learning sessions and after training stopped.

In addition, the researchers found that after formation of the second spine in a cluster, the first spine grew larger. The size of the spine head correlates with the strength of the synapse. "We found that formation of a second connection is correlated with a strengthening of the first connection, which suggests that they are likely to be involved in the same circuitry," Zuo said. "The clustering of synapses may serve to magnify the strength of the connections."

Another part of the study also supported the idea that the clustered synapses are involved in neural circuits specific to the task being learned. The researchers studied mice trained first in one task and then in a different task. Instead of grabbing a seed, the mice had to learn how to handle a piece of capellini pasta. Both tasks induced the formation of clustered spines, but spines formed during the learning of different tasks did not cluster together.

The researchers also looked at mice that were challenged with new motor tasks every day, but did not repeat the same task over and over like the ones trained in seed-grabbing or capellini-handling. These mice also grew lots of new dendritic spines, but few of the new spines were clustered.

"Repetitive activation of the same cortical circuit is really important in learning a new task," Zuo said. "But what is the optimal frequency of repetition? Ultimately, by studying the relationship between synapse formation and learning, we want to find out the best way to induce new memories."

The study used mice that had been genetically altered to make a fluorescent protein within certain neurons in the motor cortex. The researchers used a special microscopy technique (two-photon microscopy) to obtain images of those neurons near the surface of the brain. The noninvasive imaging technique enabled them to view changes in individual brain cells of the mice before, during, and after learning a new behavior.


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In addition to Zuo and first author Min Fu, the coauthors of the paper include UCSC graduate student Xinzhu Yu and Stanford University biologist Ju Lu. This research was supported by grants from the Dana Foundation and the National Institute of Mental Health.

Mom's Love Good for Child's Brain

School-age children whose mothers nurtured them early in life have brains with a larger hippocampus, a key structure important to learning, memory and response to stress LCSW Continuing Education

The new research, by child psychiatrists and neuroscientists at Washington University School of Medicine in St. Louis, is the first to show that changes in this critical region of children's brain anatomy are linked to a mother's nurturing.

Their research is published online in the Proceedings of the National Academy of Sciences Early Edition.

"This study validates something that seems to be intuitive, which is just how important nurturing parents are to creating adaptive human beings," says first author Joan L. Luby, MD. "I think the public health implications suggest that we should pay more attention to parents' nurturing, and we should do what we can as a society to foster these skills because clearly nurturing has a very, very big impact on later development."

The brain-imaging study involved children ages 7 to 10 who had participated in an earlier study of preschool depression that Luby and her colleagues began about a decade ago. That study involved children, ages 3 to 6, who had symptoms of depression, other psychiatric disorders or were mentally healthy with no known psychiatric problems.

As part of the initial study, the children were closely observed and videotaped interacting with a parent, almost always a mother, as the parent was completing a required task, and the child was asked to wait to open an attractive gift. How much or how little the parent was able to support and nurture the child in this stressful circumstance — which was designed to approximate the stresses of daily parenting — was evaluated by raters who knew nothing about the child's health or the parent's temperament.

"It's very objective," says Luby, professor of child psychiatry. "Whether a parent was considered a nurturer was not based on that parent's own self-assessment. Rather, it was based on their behavior and the extent to which they nurtured their child under these challenging conditions."

The study didn't observe parents and children in their homes or repeat stressful exercises, but other studies of child development have used similar methods as valid measurements of whether parents tend to be nurturers when they interact with their children.

For the current study, the researchers conducted brain scans on 92 of the children who had had symptoms of depression or were mentally healthy when they were studied as preschoolers. The imaging revealed that children without depression who had been nurtured had a hippocampus almost 10 percent larger that children whose mothers were not as nurturing.

"For years studies have underscored the importance of an early, nurturing environment for good, healthy outcomes for children," Luby says. "But most of those studies have looked at psychosocial factors or school performance. This study, to my knowledge, is the first that actually shows an anatomical change in the brain, which really provides validation for the very large body of early childhood development literature that had been highlighting the importance of early parenting and nurturing. Having a hippocampus that's almost 10 percent larger just provides concrete evidence of nurturing's powerful effect."

Luby says the smaller volumes in depressed children might be expected because studies in adults have shown the same results. What did surprise her was that nurturing made such a big difference in mentally healthy children.

"We found a very strong relationship between maternal nurturing and the size of the hippocampus in the healthy children," she says.

Although 95 percent of the parents whose nurturing skills were evaluated during the earlier study were biological mothers, the researchers say that the effects of nurturing on the brain are likely to be the same, for any primary caregiver — whether they are fathers, grandparents or adoptive parents.

The fact that the researchers found a larger hippocampus in the healthy children who were nurtured is striking, Luby says, because the hippocampus is such an important brain structure.

When the body faces stresses, the brain activates the autonomic nervous system, an involuntary system of nerves that controls the release of stress hormones. Those hormones help us cope with stress by increasing the heart rate and helping the body adapt. The hippocampus is the main brain structure involved in that response. It's also key in learning and memory, and larger volumes would suggest a link to improved performance in school, among other things.

Past animal studies have indicated that a nurturing mother can influence brain development, and many studies in human children have identified improvements in school performance and healthier development in children raised in a nurturing environment. But until now, there has not been solid evidence linking a nurturing parent to changes in brain anatomy in children.

"Studies in rats have shown that maternal nurturance, specifically in the form of licking, produces changes in genes that then produce changes in receptors that increase the size of the hippocampus," Luby says. "That phenomenon has been replicated in primates, but it hasn't really been clear whether the same thing happens in humans. Our study suggests a clear link between nurturing and the size of the hippocampus."

She says educators who work with families who have young children may improve school performance and child development by not only teaching parents to work on particular tasks with their children but by showing parents how to work with their children.

"Parents should be taught how to nurture and support their children. Those are very important elements in healthy development," Luby says.

Luby JL, Barch DM, Belden A, Gaffrey MS, Tillman R, Babb C, Nishino T, Suzuki H, Botteron KN. Maternal support in early childhood predicts larger hippocampal volumes at school age. Proceedings of the National Academy of Sciences Early Edition, Jan. 30, 2012. www.pnas.org/cgi/doi/10.1073/pnas.1118003109.

Funding for this research comes from grants awarded by the National Institute of Mental Health of the National Institutes of Health (NIH).

Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

Gene Regulator in Brain’s Executive Hub Tracked Across Lifespan – NIH study

Mental illness suspect genes are among the most environmentally responsive

For the first time, scientists have tracked the activity, across the lifespan, of an environmentally responsive regulatory mechanism that turns genes on and off in the brain’s executive hub. Among key findings of the study by National Institutes of Health scientists: genes implicated in schizophrenia and autism turn out to be members of a select club of genes in which regulatory activity peaks during an environmentally-sensitive critical period in development. The mechanism, called DNA methylation, abruptly switches from off to on within the human brain’s prefrontal cortex during this pivotal transition from fetal to postnatal life. As methylation increases, gene expression slows down after birth.

Epigenetic mechanisms like methylation leave chemical instructions that tell genes what proteins to make – what kind of tissue to produce or what functions to activate. Although not part of our DNA, these instructions are inherited from our parents. But they are also influenced by environmental factors, allowing for change throughout the lifespan.

“Developmental brain disorders may be traceable to altered methylation of genes early in life,” explained Barbara Lipska, Ph.D., a scientist in the NIH’s National Institute of Mental Health (NIMH) and lead author of the study. “For example, genes that code for the enzymes that carry out methylation have been implicated in schizophrenia. In the prenatal brain, these genes help to shape developing circuitry for learning, memory and other executive functions which become disturbed in the disorders. Our study reveals that methylation in a family of these genes changes dramatically during the transition from fetal to postnatal life – and that this process is influenced by methylation itself, as well as genetic variability. Regulation of these genes may be particularly sensitive to environmental influences during this critical early life period.”

Lipska and colleagues report on the ebb and flow of the human prefrontal cortex’s (PFC) epigenome across the lifespan, February 2, 2012, online in the American Journal of Human Genetics.

“This new study reminds us that genetic sequence is only part of the story of development. Epigenetics links nurture and nature, showing us when and where the environment can influence how the genetic sequence is read,” said NIMH director Thomas R. Insel, M.D.

In a companion study published last October, the NIMH researchers traced expression of gene products in the PFC across the lifespan. The current study instead examined methylation at 27,000 sites within PFC genes that regulate such expression. Both studies examined post-mortem brains of non-psychiatrically impaired individuals ranging in age from two weeks after conception to 80 years old CADC I and II Continuing Education

In most cases, when chemicals called methyl groups attach to regulatory regions of genes, they silence them. Usually, the more methylation, the less gene expression. Lipska’s team found that the overall level of PFC methylation is low prenatally when gene expression is highest and then switches direction at birth, increasing as gene expression plummets in early childhood. It then levels off as we grow older. But methylation in some genes shows an opposite trajectory. The study found that methylation is strongly influenced by gender, age and genetic variation.

For example, methylation levels differed between males and females in 85 percent of X chromosome sites examined, which may help to explain sex differences in disorders like autism and schizophrenia.

Different genes – and subsets of genes – methylate at different ages. Some of the suspect genes found to peak in methylation around birth code for enzymes, called methytransferases, that are over-expressed in people with schizophrenia and bipolar disorder. This process is influenced, in turn, by methylation in other genes, as well as by genetic variation. So genes associated with risk for such psychiatric disorders may influence gene expression through methylation in addition to inherited DNA.

Scientists worldwide can now mine a newly created online database of PFC lifespan DNA methylation from the study. The data are accessible to qualified researchers at: http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000417.v2.p1. BrainCloud, a web browser application developed by NIMH to interrogate the study data, can be downloaded at http://BrainCloud.jhmi.edu.

Two representative genes show strikingly opposite trajectories of PFC methylation across the lifespan. Each dot represents a different brain. Usually, the more methylation, the less gene expression.
Source: Barbara Lipska, Ph.D., NIMH Clinical Brain Disorders Branch


A representative gene showing how sex can influence levels of methylation across the lifespan. Each dot represents a different brain.
Source: Barbara Lipska, Ph.D., NIMH Clinical Brain Disorders Branch

Reference:

Numata S, Ye T, Hyde TM, Guitart-Navarro X, Tao R, Wininger M, Colantuoni C, Weinberger DR, Kleinman JE, Lipska BK. DNA Methylation Signatures in Development and Aging of the Human Prefrontal Cortex. American Journal of Human Genetics, 2011. Feb 2.

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The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.

Ethnic Disparities Persist in Depression Diagnosis and Treatment Among Older Americans

Older racial and ethnic minorities living in the community are less likely to be diagnosed with depression than their white counterparts, but are also less likely to get treated, according to a recent NIMH-funded analysis published online ahead of print December 15, 2011, in the American Journal of Public Health.


Source: iStock Photo

Background

Depression is a significant health concern for older adults, regardless of ethnic or racial status. Previous studies have found racial and ethnic differences in the diagnosis and treatment of depression among the general population.

Using 2001-2005 data from the nationally representative Medicare Current Beneficiary Survey (MCBS), Ayse Akincigil Ph.D., of Rutgers University and colleagues examined rates of depression diagnosis and treatment among older adults living in the community. The survey asked questions about health care use and costs, insurance coverage beyond Medicare, access to care, and use of services.

Results

The survey found that about 6.4 percent of whites, 4.2 percent of African Americans, and 7.2 percent of Hispanics were diagnosed with depression. Among those diagnosed, 73 percent of whites received treatment (either with antidepressants, psychotherapy or both), while 60 percent of African Americans received treatment and 63.4 percent of Hispanics received treatment. These kinds of diagnosis and treatment differences are consistent with previous studies, the researchers noted. They also noted pronounced differences in socioeconomic status and quality of insurance coverage across ethnicities. Fewer whites reported having low incomes than ethnic minorities. However, these differences did not appear to account for the disparities in diagnosis or treatment rates.

Significance

The findings are consistent with the notion that depression continues to be under-recognized and undertreated among older minorities. According to the researchers, future research should investigate cultural factors such as help-seeking patterns, stigma, and patient attitudes and knowledge about depression as potential factors contributing to the disparities. For instance, ethnic minorities may be less likely to seek help for a mood disorder, and those with lower incomes may have more difficulty gaining access to specialized health care. In addition, they may be more likely to seek help from nonmedical providers, such as pastors or lay counselors, according to the researchers. Other research has suggested that minorities tend to cite stigma or shame associated with having a mental disorder as a reason for not seeking help for depression.

Differences in diagnosis rates may also reflect the notion that African Americans tend to have a greater sense of distrust of doctors in general compared to white patients, said the researchers. In addition, minority patients also may be more likely to present with more physical aspects of depression such as sleep problems or pain, rather than mood or cognitive symptoms, which can complicate detection and diagnosis of depression.

What’s Next

The researchers suggest possible ways to minimize the disparities in depression diagnosis and treatment among older minorities. For instance, psychiatrists and other health care workers could be offered public financial incentives for practicing in poorer communities where depressed older people may go untreated. In addition, adding cross-cultural education into professional training opportunities for health care workers could further reduce disparities. In the meantime, promising approaches such as universal depression screening programs could be implemented, the researchers concluded Nursing CEUs

Citation

Akincigil A, Olfson M, Siegel M, Zurlo K, Walkup J, Crystal S. Racial and ethnic disparities in depression care in community-dwelling elderly in the United States. American Journal of Public Health. Online ahead of print Dec. 15, 2011.

Autism may be linked to abnormal immune system characteristics and novel protein fragment

University of South Florida researchers made the discoveries using mouse models of autism

Tampa, FL (Jan 3, 2012) – Immune system abnormalities that mimic those seen with autism spectrum disorders have been linked to the amyloid precursor protein (APP), reports a research team from the University of South Florida's Department of Psychiatry and the Silver Child Development Center.

The study, conducted with mouse models of autism, suggests that elevated levels of an APP fragment circulating in the blood could explain the aberrations in immune cell populations and function – both observed in some autism patients. The findings were recently published online in the Journal of the Federation of American Societies for Experimental Biology nursing ceus.

The USF researchers concluded that the protein fragment might be both a biomarker for autism and a new research target for understanding the physiology of the disorder.

"Autism affects one in 110 children in the United States today," said research team leader Jun Tan, MD, PhD, professor of psychiatry and the Robert A. Silver Chair, Rashid Laboratory for Developmental Neurobiology at USF's Silver Child Development Center. "While there are reports of abnormal T-cell numbers and function in some persons affected with autism, no specific cause has been identified. The disorder is diagnosed by behavioral observation and to date no associated biomarkers have been identified."

"Not only are there no associated biomarkers, but the prognosis for autism is poor and the costs associated with care are climbing," said Francisco Fernandez, MD, department chair and head of the Silver Center. "The work of Dr. Tan and his team is a start that may lead to earlier diagnosis and more effective treatments."

The amyloid precursor protein is typically the focus of research related to Alzheimer's disease. However, recent scientific reports have identified elevated levels of the particular protein fragment, called, sAPP-α, in the blood of autistic children. The fragment is a well-known growth factor for nerves, and studies imply that it plays a role in T-cell immune responses as well.

To study the autism-related effects of this protein fragment on postnatal neurodevelopment and behavior, Dr. Tan and his team inserted the human DNA sequence coding for the sAPP-α fragment into the genome of a mouse model for autism. While the studies are ongoing, the researchers documented the protein fragment's effects on the immune system of the test mice.

"We used molecular biology and immunohistochemistry techniques to characterize T-cell development in the thymus and also function in the spleen of the test animals," Dr. Tan said. "Then we compared transgenic mice to their wild-type littermates."

The researchers found that increased levels of sAPP-α in the transgenic mice led to increased cytotoxic T-cell numbers. The investigators also discovered subsequent impairment in the recall function of memory T-cells in the test mice, suggesting that the adaptive immune response is negatively affected in the presence of high levels of the protein fragment.

"Our work suggests that the negative effects of elevated sAPP-α on the adaptive immune system is a novel mechanism underlying certain forms of autism," concluded Dr. Tan, who holds the Silver Chair in Developmental Neurobiology. "The findings also add support to the role of sAPP-α in the T-cell response."


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Other researchers involved in the study were Antoinette Bailey, Dr. Huayan Hou, Dr. Demian Obregon, Jun Tian, Dr. Yuyan Zhu, Dr. Qiang Zou, Dr. William Nikolic, Dr. Michael Bengston, Dr. Takashi Mori (Saitama Medical Center/Saitama Medical University, Japan) and Dr. Tanya Murphy.

The work was supported by the Silver Endowment and a grant from the National Institutes of Health/National Institute of Mental Health.

Citation: Aberrant T-lymphocyte development and function in mice overexpressing human secreted amyloid precursor protein-α: implications for autism; A. Bailey, H. Hou, D. Obregon, J. Tian, Y. Zhu, Q. Zou, W. Nikolic, M. Bengston, T. Mori, T. Murphy, J. Tan; The FASEB Journal; published online Nov. 15, 2011.

USF Health's mission is to envision and implement the future of health. It is the partnership of the USF Health Morsani College of Medicine, the College of Nursing, the College of Public Health, the College of Pharmacy, the School of Biomedical Sciences and the School of Physical Therapy and Rehabilitation Sciences; and the USF Physician's Group. The University of South Florida is a global research university ranked 34th in federal research expenditures for public universities.

ELDERLY CAN BE AS FAST AS YOUNG IN SOME BRAIN TASKS, STUDY SHOWS

COLUMBUS, Ohio – Both children and the elderly have slower response times when they have to make quick decisions in some settings.

But recent research suggests that much of that slower response is a conscious choice to emphasize accuracy over speed.

In fact, healthy older people can be trained to respond faster in some decision-making tasks without hurting their accuracy – meaning their cognitive skills in this area aren’t so different from younger adults.


Roger Ratcliff
“Many people think that it is just natural for older people’s brains to slow down as they age, but we’re finding that isn’t always true,” said Roger Ratcliff, professor of psychology at Ohio State University and co-author of the studies.

“At least in some situations, 70-year-olds may have response times similar to those of 25-year olds.”

Ratcliff and his colleagues have been studying cognitive processes and aging in their lab for about a decade. In a new study published online this month in the journal Child Development, they extended their work to children.

Ratcliff said their results in children are what most scientists would have expected: very young children have slower response times and poorer accuracy compared to adults, and these improve as the children mature.

But the more interesting finding is that older adults don’t necessarily have slower brain processing than younger people, said Gail McKoon, professor of psychology at Ohio State and co-author of the studies.

“Older people don’t want to make any errors at all, and that causes them to slow down. We found that it is difficult to get them out of the habit, but they can with practice,” McKoon said.

Researchers uncovered this surprising finding by using a model developed by Ratcliff that considers both the reaction time and the accuracy shown by participants in speeded tasks. Most models only consider one of these variables.

“If you look at aging research, you find some studies that show older people are not impaired in accuracy, but other studies that show that older people do suffer when it comes to speed. What this model does is look at both together to reconcile the results,” Ratcliff said.

Ratcliff, McKoon and their colleagues have used several of the same experiments in children, young adults and the elderly.

In one experiment, participants are seated in front of a computer screen. Asterisks appear on the screen and the participants have to decide as quickly as possible whether there is a “small” number (31-50) or a “large” number (51-70) of asterisks. They press one of two keys on the keyboard, depending on their answer.

In another experiment, participants are again seated in front of a computer screen and are shown a string of letters. They have to decide whether those letters are a word in English or not. Some strings are easy (the nonwords are a random string of letters) and some are hard (the nonwords are pronounceable, such as “nerse”).

In the Child Development study, the researchers used the asterisk test on second and third graders, fourth and fifth graders, ninth and tenth graders, and college-aged adults. Third graders and college-aged adults participated in the word/nonword test.

The results showed that there was a rise in accuracy and decrease in response time on both tasks from the second and third-graders to the college-age adults.

The younger children took longer than older children and adults to respond in the experiment, Ratcliff said. They, like the elderly, were taking longer to make up their mind. But the younger children were also less accurate than younger adults in this study.

“Younger children are not able to make as good of use of the information they are presented, so they are less accurate,” Ratcliff said. “That improves as they mature.”

Older adults show a different pattern. In a study published in the journal Cognitive Psychology, Ratcliff and colleagues compared college-age subjects, older adults aged 60-74, and older adults aged 75-90. They used the same asterisk and word/nonword tests that were in the Child Development study. They found that there was little difference in accuracy among the groups, even the oldest of participants.

However, the college students had faster response times than did the 60-74 year olds, who were faster than the 75-90 year olds. Continuing Education for Counselors






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“If you look at aging research, you find some studies that show older people are not impaired in accuracy, but other studies that show that older people do suffer when it comes to speed. What this model does is look at both together to reconcile the results.”

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But the slower response times are not all the result of a decline in skills among older adults. In a previous study, the researchers encouraged older adults to go faster on these same tests. When they did, the difference in their response times compared to college-age students decreased significantly.

“For these simple tasks, decision-making speed and accuracy is intact even up to 85 and 90 years old,” McKoon said.

That doesn’t mean there are no effects of aging on decision-making speed and accuracy, Ratcliff said. In a study in the Journal of Experimental Psychology: General, Ratcliff, McKoon and another colleague found (like in studies from other laboratories) that accuracy for “associative memory” does decline as people age. For example, older people were much less likely to remember if they had studied a pair of words together than did younger adults.

But Ratcliff said that, overall, their research suggests there should be greater optimism about the cognitive skills of seniors.

“The older view was that all cognitive processes decline at the same rate as people age,” Ratcliff said.

“We’re finding that there isn’t such a uniform decline. There are some things that older people do nearly as well as young people.”

Ratcliff co-authored the Child Development paper with Jessica Love and John Opfer of Ohio State and Clarissa Thompson of the University of Oklahoma. Ratcliff and McKoon co-authored the Cognitive Psychology and Journal of Experimental Psychology: General papers with Anjali Thapar of Bryn Mawr College.

Some of the research was supported with grants from the National Institute on Aging and the National Institute of Mental Health.

Turning on Dormant Gene May Hold Key for Correcting a Neurodevelopmental Defect

Finding Shows Therapeutic Potential of Small-Molecule Targeting Strategy

Scientists working in cell culture and in mice have been able to correct the loss of gene activity underlying a rare but severe developmental disorder by turning on a gene that is normally silenced in brain cells. Further testing of the identified compound that activates the gene will determine whether it has potential as a genetically-based treatment for the disorder, Angelman syndrome.

Background

Infants with Angelman syndrome appear normal at birth, but show developmental delays by 6 to 12 months. Features of the disorder include impaired speech, seizures, hyperactivity, and motor difficulties. No effective treatment exists CADC I & II Continuing Education

In the late 1990s, researchers found that the disorder results from changes or deletions in the maternal gene for the enzyme ubiquitin protein ligase E3A (Ube3a). Most genes are inherited in sets of two, one from the mother and one from the father. In some cases, either the maternal or paternal gene is silenced, or prevented from being translated into protein. This normal silencing based on inheritance from a mother or father is called imprinting. The Ube3a gene is an example of genetic imprinting, as the paternal gene is normally silenced in neurons. With the maternal gene out of action, infants with Angelman syndrome lack the enzyme, leading to changes in the brain that underlie the symptoms of the disorder.

This Study

This research is reported online in the journal Nature, and was carried out by scientists at the University of North Carolina School of Medicine at Chapel Hill, led by the labs of Ben Philpot, Bryan Roth, and Mark Zylka. In an effort to restore the absent Ube3a enzyme in neurons, the research team screened thousands of compounds for their ability to “wake up” the paternal Ube3a gene. The investigators used neurons from genetically engineered mice to test whether compounds could activate the gene; the neurons fluoresce if the paternal Ube3a gene is expressed, or translated into protein. The team screened 2,306 candidate small molecules from multiple molecular libraries. If fluorescence was detected, that meant that the test compound activated the Ube3a gene. The screening and access to the molecular libraries was made possible through NIMH’s Psychoactive Drug Screening Program, funded by contract to perform pharmacological and functional screening of novel compounds. Bryan Roth at UNC Chapel Hill is the project director and a coauthor of the Nature paper.

The investigators found that a class of compounds—topoisomerase inhibitors—could unsilence the paternal gene. They chose one, topotecan, and tested it to see whether it could do the same thing in vivo in a mouse. They administered topotecan directly into the brain and later into spinal fluid; in both cases it was able to activate paternal Ube3a. Activation persisted for 12 weeks after delivery of the compound had stopped.

Significance

"This is the first time anyone has used a small molecule to successfully target activation of a disease-relevant gene," said senior author Benjamin Philpot. "The work demonstrates that turning on a dormant gene could represent a therapeutic intervention for Angelman syndrome."

NIMH helped to fund this project and has issued a grant to the UNC team to continue studies of topotecan, initially in mice. Although topotecan is already in use in both children and adults as a cancer chemotherapeutic agent, further testing is essential to determine the dosage of the agent that would be needed to be effective, the best means of administering the medication, and whether side-effects at the necessary dosage level are within a range that make it feasible to use. The authors emphasize that much work remains before this or related agents can or should be used for treatment of this condition.

Reference

Huang, H.-S., Allen, J., Mabb, A., King, I., Miriyala, J., Taylor-Blake, B., Sciaky, N., Dutton, J. Jr., Lee, H.M., Chen, X., Jin, J. Bridges, A., Zylka, M., Roth, B., Philpot, B. Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. Nature. Published online ahead of print December 21, 2011, doi: 10.1038/nature10726.


This image shows Ube3a staining in a neurotypical mouse brain and its absence in the Angelman syndrome model mouse brain.

Source: Ben Philpot, Ph.D., University of North Carolina School of Medicine