TAG: "Autism"

UC Davis scientist receives International Sisley-Lejeune Foundation Award


Randi Hagerman honored for her work developing treatments for fragile X syndrome.

By Phyllis Brown, UC Davis

Randi Hagerman receiving the International Sisley-Lejeuen Award 2014 in Paris.

Randi Hagerman, medical director of the UC Davis MIND Institute, has received the prestigious International Sisley-Lejeune Award 2014 from the Paris-based Jérôme Lejeune Foundation, for her groundbreaking work developing targeted treatments for individuals with fragile X syndrome, a leading cause of intellectual disability and the leading single-gene cause of autism spectrum disorder.

The award recognizes significant accomplishments in therapeutic research for Down syndrome or other genetic intellectual disabilities for researchers who have ‘contributed to creating knowledge of these pathologies and the discovery of treatments and cures.’

The Jérôme Lejeune Foundation was founded by Jérôme Lejeune, discoverer of the cause of Down syndrome, which in 1958 he renamed trisomy 21, to accurately describe the genetic abnormality. Hagerman received the award in Paris on March 10, in an event timed to coincide with World Down Syndrome Awareness Day. The award comes with a €30,000, or $33,855 prize, and a lecture.

“I am very positive about new targeted treatments that have the potential to reverse intellectual disability at a variety of ages, including childhood, adolescence and even in adulthood. My work will continue for this very important goal,” said Hagerman, distinguished professor of pediatrics and Endowed Chair in Fragile X Research and Treatment.

Hagerman is one of the world’s leading physician-scientists investigating fragile X-related disorders, including fragile X syndrome and fragile X-associated tremor/ataxia syndrome, or FXTAS, a condition affecting primarily older men that she discovered with her husband, Paul Hagerman, in 2001. In 1984 she founded the National Fragile X Foundation in the United States.

Hagerman said during her acceptance speech that she is hopeful that her ongoing trials of investigational drugs, such as ganaxolone, mGluR5 antagonists, minocycline, and sertraline, eventually may improve language, attention, socialization and learning in people with fragile X syndrome and other genetic conditions, such as Angelman syndrome. This work, she said “leads the way for treatments that may reverse neurobiological abnormalities in autism and many other neurodevelopmental disorders.” These treatments must be coupled with educational programs to ensure that patients may take advantage of their improved cognitive strengths.

Hagerman is director of the MIND Institute’s Fragile X Research and Treatment Center. She is the recipient of numerous honors, including the Jarrett Cole Clinical Award from the National Fragile X Foundation for dedicated service to families in the worldwide fragile X community; the Bonfils-Stanton Foundation Award for her pioneering work in fragile X disorders; and the Distinguished Scholarly Public Service Award from UC Davis. In 2008 she received a Lifetime Achievement Award from the National Fragile X Foundation and, in 2014, she received the C. Anderson Aldrich Award from the American Academy of Pediatrics, for her outstanding contributions to the field of child development.

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Blood-based genetic biomarkers ID young boys with autism


Proof-of-principle method suggests much-earlier diagnoses could be done with clinic test.

By Scott LaFee, UC San Diego

In a study published in the current online issue of JAMA Psychiatry, an international team of scientists, led by researchers at the UC San Diego School of Medicine, report finding a highly accurate blood-based measure that could lead to development of a clinical test for autism spectrum disorder (ASD) risk in males as young as 1 to 2 years old.

The test could be done in community pediatric settings. The degree of accuracy, they said, outperforms other behavioral and genetic screens for infants and toddlers with ASD described in literature.

The causes of ASD are complex and diverse, making it difficult to conclusively diagnose the disease much before a child’s fourth year of life. Indeed, the median age of diagnosis in the United States is 53 months.

“A major challenge is the difficulty of accurately diagnosing ASD, which is very heterogeneous, at an early enough age to implement the most effective treatment,” said principal investigator Eric Courchesne, Ph.D., professor of neurosciences and director of the Autism Center of Excellence at the UC San Diego School of Medicine.

In the proof-of-principle study, Courchesne, first author Tiziano Pramparo, Ph.D., and colleagues identified blood-based genomic biomarkers that differentiated toddlers with ASD, ranging in age from 1 to 4 years old, from a control group of toddlers without ASD. Blood samples were taken at the child’s initial clinical intake. Importantly, the control group consisted of a mix of young boys commonly seen in community clinics, with typical development, mild language delay, transient language delay and global developmental delay. Against this control group, the researchers identified a genetic signature that identified 83 percent of ASD toddlers.

The study used an unbiased systems biology-based method to search for genes and gene pathways in blood samples that best distinguished ASD infants and toddlers from typically developing toddlers and toddlers with non-autism developmental delays. Specifically, the researchers measured leukocyte (white blood cell) RNA expression levels.

“Ideally, biomarkers come from tissue affected, but in ASD this is the brain, which is obviously an inaccessible tissue,” said Courchesne. “Peripheral blood of living ASD infants and toddlers is an important alternative, and obtaining blood samples is routine and safe and, thus, is a preferable and accessible tissue for identifying signatures of ASD that could be used in clinical screening and follow-up evaluations.”

Pramparo, an associate research scientist at the UC San Diego Autism Center of Excellence, said blood is expected to carry autism-relevant molecular signatures that can be used to detect the disorder at very young ages. It might also reflect aspects of the disrupted biology underlying neural defects.

In fact, the researchers found gene expression differences between ASD and non-ASD in genes related to translation and immune/inflammation functions, as well as cell adhesion and cell cycle. These “ASD signature classifier” genes are among those that can have effect on early brain development.

“New studies point to autism beginning in the womb,” said Courchesne, who, with colleagues, published one such widely reported study last year detailing disrupted brain development in post-mortem brains of autistic children. “Our present study shows examination of the gene expression profiles at the very early age of initial clinical detection reveals both strong evidence of early biological processes in ASD and abnormal signals with the potential to serve as an early, practical biomarker of risk for the disorder in general pediatric settings.”

The scientific team conducted two different analyses of blood samples involving two cohorts of study participants: 147 toddlers (91 with ASD, 56 control) in the first group, 73 toddlers (44 ASD, 29 control) in the second group. The first assay identified an ASD genomic signature 83 percent of the time; the second had a 75 percent accuracy rate.

Young male toddlers with autism were the focus of the study because autism is far more prevalent in males.

“The genetics and molecular bases of autism may differ somewhat in affected males and females,” said Pramparo. “We reasoned, therefore, that different signatures might need to be discovered and developed in each gender in ASD.”

It was simpler to begin with boys.

“Autism is four times more common in males,” said Courchesne, “and so we were able to more quickly recruit and test samples of autism males than autism females. Our current work is aimed at recruiting sufficiently large samples of females to begin work to discover possible gene expression markers for them.”

Courchesne emphasized that this was a first step toward a possible means of diagnosing autism much earlier than current methodologies, one that would greatly boost the efficacy of intervention and remedial treatments.

Though only proof-of-principle, Courchesne said the findings are encouraging. Next steps involve further refinement of the process and identification of diagnostic risk markers for females.

“As we write in the paper, our study showed that a blood-based clinical test for at-risk male infants and toddlers could be refined and routinely implemented in pediatric diagnostic settings.”

Co-authors include Karen Pierce, Cynthia Carter Barnes, Steven Marinero, Clelia Ahrens-Barbeau and Linda Lopez, UC San Diego Autism Center of Excellence; Michael V. Lombardo, University of Cambridge and University of Cyprus; Sarah S. Murray, Scripps Translational Sciences Institute; and Ronghui Xu, UCSD.

Funding for this research came, in part, from the National Institutes of Health (grants P50-MH081755, R01-MH036840, R01-MH080134, 1U54RR025204, 1UL1RR031980-01) and UC San Diego (grant KL2T00099).

Disclosure: Pramparo and Courchesne have a patent application pending that includes data from this study.

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Newborn foals may offer clues to autism


Common link, researchers suggest, may be abnormal levels of naturally occurring neurosteroids.

Veterinary researchers at the University of California, Davis, are teaming up with their colleagues in human medicine to investigate a troubling disorder in newborn horses and are exploring possible connections to childhood autism. The common link, the researchers suggest, may be abnormal levels of naturally occurring neurosteroids.

The horse disorder, known as neonatal maladjustment syndrome, has puzzled horse owners and veterinarians for a century. Foals affected by the disorder seem detached, fail to recognize their mothers and have no interest in nursing.

“The behavioral abnormalities in these foals seem to resemble some of the symptoms in children with autism,” said John Madigan, a UC Davis veterinary professor and expert in equine neonatal health.

The maladjustment syndrome in foals also caught the attention of Isaac Pessah, a professor of molecular biosciences at the UC Davis School of Veterinary Medicine and a faculty member of the UC Davis MIND Institute, who investigates environmental factors that may play a role in the development of autism in children.

“There are thousands of potential causes for autism, but the one thing that all autistic children have in common is that they are detached,” Pessah said

Madigan, Pessah and other researchers in veterinary and human medicine recently formed a joint research group and secured funding to investigate links between the two conditions.

(See news feature story. A press kit, including video b-roll and high-resolution still images, is available.)

Maladjusted foal syndrome

In newborn foals, neonatal maladjustment syndrome, or dummy foal syndrome, occurs in 3 to 5 percent of live births. With around-the-clock bottle or tube feeding plus intensive care in a veterinary clinic for up to a week or 10 days, 80 percent of the foals recover. But for horse owners, that level of care is grueling and costly.

For years, the syndrome has been attributed to hypoxia — insufficient oxygen during the birthing process. Madigan and UC Davis veterinary neurologist Monica Aleman began sleuthing around for other potential causes, however, noting that hypoxia usually causes serious, permanent damage, while most foals with the maladjustment syndrome survive with no lingering health problems.

One of their prime suspects was a group of naturally occurring neurosteroids, which are key to sustaining pregnancies in horses, especially in keeping the foal “quiet” before birth.

Foals remain quiet in the womb

“Foals don’t gallop in utero,” Madigan is fond of saying, pointing out the dangers to the mare if a four-legged, hoofed fetus were to suddenly become active in the womb. The prenatal calm is made possible, he explains, by neurosteroids that act as sedatives for the unborn foal.

However, immediately after birth, the infant horse must make an equally important transition to consciousness. In nature, a baby horse would be easy prey for many natural enemies, so the foal must be ready to run just a few hours after it is born.

In short, somewhere between the time a foal enters the birth canal and the moment it emerges from the womb, a biochemical “on switch” must be flicked that enables the foal to recognize the mare, nurse and become mobile. Madigan and Aleman suspect that the physical pressure of the birthing process may be that important signal.

“We believe that the pressure of the birth canal during the second stage of labor, which is supposed to last 20 to 40 minutes, is an important signal that tells the foal to quit producing the sedative neurosteroids and ‘wake up,’ ” Madigan said.

Neurosteroids persist in the bloodstream

The theory, he says, is supported by the fact that the maladjusted foal syndrome appears more frequently in horses that were delivered via cesarean section or experienced unusually rapid births. Perhaps those foals do not experience significant physical pressure to trigger the change in neurosteroids, Madigan said.

Furthermore, the research team has found for the first time that sedative neurosteroids persist, and their levels often rise, in the bloodstream of foals born with symptoms of the maladjustment syndrome. These neurosteroids are known to be able to cross the blood-brain barrier and impact the central nervous system, acting on the same receptor as do sedatives and anesthetics.

The researchers also have demonstrated that maladjustment symptoms can be brought on temporarily in normal, healthy foals by administering short infusions of a neurosteroid called allopregnanolone. When the neurosteroid levels drop, the foals return to their normal state.

Foals ‘wake up’ with gentle harness pressure

Amazingly, the veterinary researchers have found that they can reduce maladjustment symptoms in foals by using several loops of a soft rope to gently squeeze the foal’s upper torso and mimic the pressure normally experienced in the birth canal. When pressure is applied with the rope, the foal lies down and appears to be asleep.

After 20 minutes — about the same time a foal would spend in the birth canal — the rope is loosened and the squeeze pressure released. In initial cases, the foals have responded well to the procedure and recovered, some rising to their feet within minutes and then bounding over to join the mare and nurse.

The researchers suspect that the pressure triggers biochemical changes in the central nervous system that are critical for transitioning the foal from a sleeplike state in the womb to wakefulness at birth.

While larger studies are underway, the researchers have presented their results at national and international meetings of equine veterinarians, and many veterinarians and clinics are treating maladjusted foals with the squeeze procedure — now called the Madigan Foal Squeeze Procedure.

Madigan cautions that, in spite of the strong observational effects, a larger, controlled clinical trial of national and international scope is now needed to reproduce those observed results and provide a better understanding of the mechanisms at work in the foals.

Foal behaviors resemble autism

The early findings have compelling implications for the health of newborn foals, and have caused the researchers to also explore possible links to autism, which includes a group of complex brain-development disorders. While the symptoms vary, these disorders are generally marked by difficulties with social interactions, verbal and nonverbal communication, and repetitive behaviors.

“The concept that a disruption in the transition of fetal consciousness may be related to children with autism is intriguing,” said Pessah, noting that the behaviors seen in the maladjusted foal syndrome truly are reminiscent of those in some autistic children.

He notes that some children with autism do outgrow autistic behaviors by the time they reach their teen years. Could this be a parallel to the recovery of the foals with the maladjustment syndrome?

Investigating possible links

A new group called the Comparative Neurology Research Group, consisting of veterinarians, physicians, epidemiologists and basic-science researchers, has formed to pursue further studies in this area. Madigan is working with researchers at the Stanford School of Medicine, exploring the mechanisms of post-birth transitions of consciousness related to neonatal care of infants.

Using data from the foal research, Pessah and Madigan are working with environmental epidemiologist Irva Hertz-Picciotto at the UC Davis MIND Institute to investigate neurosteroids in children with varying degrees of autism, ranging from some developmental delay to full-spectrum autism.

The researchers are exploring whether abnormal regulation of neurosteroids during the time around childbirth could be one of many factors that might contribute to autism and related neurodevelopmental disorders. A recent study has reported elevated levels of neurosteroids in children with autism spectrum disorder.

Pessah and colleagues will be looking to see whether there are alterations in blood levels of certain neurosteroids that may serve as a marker for the disorder. They caution, however, that the relationship right now is just a theory that remains to be validated or disproven.

More information about this research effort.

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Oxytocin shows promise for improving social skills in autistic mice


UCLA study could point way toward therapy for people with autism.

Daniel Geschwind, UCLA

By Mark Wheeler, UCLA

People with autism spectrum disorders have difficulty with social behavior and communication, which can make it challenging to form friendships, engage in routine conversations or pick up on the social cues that are second nature to most people. Similarly, mice with symptoms of autism show little interest in interacting or socializing with other mice.

A drug called risperidone has been shown to treat some symptoms of autism — including repetitive behaviors — in both humans and mice, but so far no medication has been found to help improve the ability to socialize.

In a study published online by the journal Science Translational Medicine, researchers at UCLA found that giving oxytocin to mice with autism-like symptoms restored their normal social behavior. Oxytocin is a neuropeptide, a type of molecule that helps neurons communicate with one another.

But perhaps the study’s biggest surprise was that early postnatal administration of the oxytocin led to longer-lasting positive effects, which continued into the animals’ adolescence and adulthood. “This suggests that there may be critical windows of time for treatment that are better than others,” said Daniel Geschwind, a UCLA professor of psychiatry, neurology and human genetics and senior author of the study.

In 2011, Geschwind and his colleagues developed a mouse model for autism spectrum disorders by knocking out a gene called contactin-associated protein-like 2, or CNTNAP2, which scientists believe plays an important role in the brain circuits responsible for language and speech. Previous research has linked common CNTNAP2 variants to a heightened risk for autism, while rare variants can lead to an inherited form of autism called cortical dysplasia-focal epilepsy syndrome.

“The oxytocin system is a key mediator of social behavior in mammals, including humans, for maternal behavior, mother–infant bonding, and social memory,” said Geschwind, who holds UCLA’s Gordon and Virginia MacDonald Distinguished Chair in Human Genetics and is the director of the Center for Autism Research and Treatment at the Semel Institute for Neuroscience and Human Behavior at UCLA. “So it seemed like a natural target for us to go after.”

The mice that were engineered for autism have fewer oxytocin neurons in the hypothalamus than other mice and lower-than-normal oxytocin levels throughout the brain. But after researchers treated them with oxytocin, the animals spent normal amounts of time interacting with other mice — the measure scientists used to gauge their sociability.

Separately, the researchers gave the mice melanocortin, an agonist that binds to specific receptors on a cell in order to activate it. They found that it caused a natural release of oxytocin from the mice’s brain cells, which also improved the mice’s sociability.

“The study shows that a primary deficit in oxytocin may cause the social problems in these mice, and that correcting this deficit can correct social behavior,” Geschwind said.

The next stage of the research, Geschwind said, will be to determine the lowest dosage of oxytocin that still proves effective. Because the mice in the study displayed symptoms similar to those of people on the autism spectrum, the researchers hope that this therapy may someday be applicable to humans.

The study was funded by the National Institute of Mental Health (R01 MH081754-02R, NIH/NS50220), the NIH Autism Centers of Excellence (HD055784-01 and 5R01-MH081754-04), the Simons Foundation Autism Research Initiative, Autism Speaks (7657), the NIH/National Institute of Neurological Disorders and Stroke (R01 NS049501 and R01 NS074312) and a McKnight Foundation Brain Disorders Award.

The study’s other authors were Olga Peñagarikano, María Lázaro, Xiao-Hong Lu, Hongmei Dong, Hoa Lam, Elior Peles, Nigel Maidment, Niall Murphy and X. William Yang, all of UCLA; Peyman Golshani of UCLA and the West Los Angeles V.A. Medical Center; and Aaron Gordon of Israel’s Weizmann Institute of Science.

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Century-old drug reverses autism-like symptoms


Suramin shows promise in fragile X mouse model.

By Scott LaFee, UC San Diego

Autism spectrum disorders (ASD) affect 1 to 2 percent of children in the United States. Hundreds of genetic and environmental factors have been shown to increase the risk of ASD. Researchers at UC San Diego School of Medicine previously reported that a drug used for almost a century to treat trypanosomiasis, or sleeping sickness, reversed environmental autism-like symptoms in mice.

Now, a new study published in this week’s online issue of Molecular Autism, suggests that a genetic form of autism-like symptoms in mice are also corrected with the drug, even when treatment was started in young adult mice.

The underlying mechanism, according to Robert K. Naviaux, M.D., Ph.D., the new study’s principal investigator and professor of medicine at UC San Diego, is a phenomenon he calls the cellular danger response (CDR). When cells are exposed to danger in the form of a virus, infection, toxin or even certain genetic mutations, they react defensively, shutting down ordinary activities and erecting barriers against the perceived threat. One consequence is that communication between cells is reduced, which the scientists say may interfere with brain development and function, leading to ASD.

Researchers treated a fragile X genetic mouse model, one of the most commonly studied mouse models of ASD, with suramin, a drug long used for sleeping sickness. The approach, called antipurinergic therapy or APT, blocked the CDR signal, allowing cells to restore normal communication and reversing ASD symptoms.

“Our data show that the efficacy of APT cuts across disease models in ASD. Both the environmental and genetic mouse models responded with a complete, or near complete, reversal of ASD symptoms,” Naviaux said. “APT seems to be a common denominator in improving social behavior and brain synaptic abnormalities in these ASD models.”

Weekly treatment with suramin in the fragile X genetic mouse model was started at 9 weeks of age, roughly equivalent to 18 years in humans. Metabolite analysis identified 20 biochemical pathways associated with symptom improvements, 17 of which have been reported in human ASD. The findings of the six-month study also support the hypothesis that disturbances in purinergic signaling – a regulator of cellular functions, and mitochondria (prime regulators of the CDR) – play a significant role in ASD.

Naviaux noted that suramin is not a drug that can be used for more than a few months without a risk of toxicity in humans. However, he said it is the first of its kind in a new class of drugs that may not need to be given chronically to produce beneficial effects. New antipurinergic medicines, he said, might be given once or intermittently to unblock metabolism, restore more normal neural network function, improve resilience and permit improved development in response to conventional, interdisciplinary therapies and natural play.

“Correcting abnormalities in a mouse is a long way from a cure in humans,” cautioned Naviaux, who is also co-director of the Mitochondrial and Metabolic Disease Center at UC San Diego, “but our study adds momentum to discoveries at the crossroads of genetics, metabolism, innate immunity, and the environment for several childhood chronic disorders. These crossroads represent new leads in our efforts to understand the origins of autism and to develop treatments for children and adults with ASD.”

Co-authors include Jane C. Naviaux, Lin Wang, Kefeng Li, A. Taylor Bright, William A. Alaynick, Kenneth R. Williams and Susan B. Powell, all at UC San Diego.

This study was supported, in part, by the Jane Botsford Johnson Foundation, the UC San Diego Christini Foundation, the UC San Diego Mitochondrial Research Fund, and the Wright Family Foundation.

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Expert in translating autism research into community practice joins UC Davis


Aubyn Stahmer, a licensed clinical psychologist, will be part of the MIND Institute.

Aubyn Stahmer, UC Davis

By Phyllis Brown, UC Davis

Aubyn Stahmer, an expert in the translation of evidence-based autism research to community-based practice and delivery, has joined the UC Davis MIND Institute as an associate professor in the Department of Psychiatry and Behavioral Sciences.

Stahmer, a licensed clinical psychologist, comes to UC Davis from UC San Diego, where she was research director of the Autism Discovery Institute at Rady Children’s Hospital, San Diego, and associate director of the Child and Adolescent Services Research Center.

“We evaluate how to take evidence-based interventions that are effective in research settings and make it possible to deliver them in settings where kids are getting usual care, in schools and early-intervention settings in the community,” Stahmer said.

She is an internationally respected expert in the use of naturalistic developmental behavioral interventions which are validated treatments for autism. Derived from developmental science and applied behavioral analysis (ABA), these interventions are play-based and child-initiated. Goals include the development of communication, language and positive social behaviors.

Stahmer is the principal investigator of two U.S. Department of Education grants designed to examine methods of translating research-based interventions in collaboration with community providers. One adapted model, called Classroom Pivotal Response Teaching, is for classroom use in children 3 to 11. Another, Project ImPACT for Toddlers, provides parent coaching for very young children at risk for autism. Stahmer will continue that research, which is based in public schools and early intervention programs, at the MIND Institute, potentially including Sacramento-area public school and community settings.

At Rady Children’s Hospital Stahmer operated a preschool program for children from 18 months to five years with autism in a setting that also included typically developing peers.

“Dr. Stahmer’s expertise and interests complement and enhance our established programs of research on evidence-based practices in autism treatment,” said Leonard Abbeduto, director of the MIND Institute. “She will extend the reach of the MIND Institute even further into our community, and so ensure we help even more families affected by autism.”

Stahmer said that she plans to work closely with Sally Rogers, professor of psychiatry and behavioral sciences and developer of the Early Start Denver Model (ESDM) approach to early autism intervention. Together they will examine methods of increasing access to evidence-based care to families of children with autism in rural and underserved areas.

“I am very excited to work with Dr. Rogers to examine new ways to increase access to ESDM in the community, both locally and internationally,” Stahmer said.

Rogers said she shares Stahmer’s enthusiasm.

“I am delighted to be able to work with such a wonderful scientist and clinician,” Rogers said. “Her research and expertise in moving interventions from the lab into the community will be a great help to all the intervention scientists at UC Davis.”

Stahmer received her bachelor’s degree from the University of Colorado, Boulder. She received her master’s and doctoral degrees from UC San Diego. She will receive an annual base salary of $126,800. Additional compensation information is available upon request.

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Multiple, short learning sessions strengthen memory formation in fragile X


UC Irvine study suggests the method could aid children with the autism-related condition.

Christine Gall and Gary Lynch found that fragile X model mice trained in three short, repetitious episodes spaced one hour apart performed as well on memory tests as normal mice. (Photo by Chris Nugent, UC Irvine)

By Tom Vasich, UC Irvine

A learning technique that maximizes the brain’s ability to make and store memories may help overcome cognitive issues seen in fragile X syndrome, a leading form of intellectual disability, according to UC Irvine neurobiologists.

Christine Gall, Gary Lynch and colleagues found that fragile X model mice trained in three short, repetitious episodes spaced one hour apart performed as well on memory tests as normal mice. These same fragile X rodents performed poorly on memory tests when trained in a single, prolonged session – which is a standard K-12 educational practice in the U.S.

“These results are dramatic and never seen before. Fragile X model mice trained using this method had memory scores equal to those of control animals,” said Gall, professor of anatomy & neurobiology and neurobiology & behavior. “Our findings suggest an easily implemented, noninvasive strategy for treating an important component of the cognitive problems found in patients with fragile X syndrome.”

Fragile X syndrome is an inherited genetic condition that causes intellectual and developmental disabilities and is commonly associated with autism. Symptoms include difficulty learning new skills or information.

It’s been known since classic 19th century educational psychology studies that people learn better when using multiple, short training episodes rather than one extended session.

Two years ago, the Lynch and Gall labs found out why. They discovered a biological mechanism that contributes to the enhancing effect of spaced training: Brain synapses – which are the connection points among neurons that transfer signals – encode memories in the hippocampus much better when activated briefly at one-hour intervals.

The researchers found that synapses have either low or high thresholds for learning-related modifications and that the high-threshold group requires hourlong delays between activation in order to store new information.

“This explains why prolonged ‘cramming’ is inefficient – only one set of synapses is being engaged,” said Lynch, professor of psychiatry & human behavior and anatomy & neurobiology. “Repeated short training sessions, spaced in time, engage multiple sets of synapses. It’s as if your brain is working at full power.”

The finding was significant, Gall added, because it demonstrated that a ubiquitous and fundamental feature of psychology can, at least in part, be explained by neurobiology.

It also gave the researchers time-sequencing rules for optimizing forms of learning dependent upon the hippocampus – utilized in the current study. Results appear in the Nov. 25 issue of Proceedings of the National Academy of Sciences.

The UCI scientists stress that the new brain-based training protocols, if applied during childhood, have the potential to offset many aspects of fragile X-related autism. “We believe that synaptic memory mechanisms are used during postnatal development to build functional brain circuits for dealing with confusing environments and social interactions,” Lynch said. “Implementing the brain-based rules during childhood training could result in lifelong benefits for patients.”

He and Gall look forward to collaborating with UCI’s Center for Autism Research & Translation to further evaluate the effect of multiple, short training episodes on learning in fragile X children.

Ronald Seese led the study as part of his work toward a Ph.D. and was assisted by Kathleen Wang and Yue Qin Yao. The research was funded by the National Science Foundation (grant 1146708), the National Institutes of Health (grants MH082042 and NS04260), and the William & Nancy Thompson Family Foundation, via UCI’s Center for Autism Research & Translation.

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Preeclampsia during mother’s pregnancy linked with greater autism risk


Likelihood of autism diagnosis even greater if mother experienced more severe disease.

By Phyllis Brown, UC Davis

Children with autism spectrum disorder (ASD) were more than twice as likely to have been exposed in utero to preeclampsia, and the likelihood of an autism diagnosis was even greater if the mother experienced more severe disease, a large study by researchers with the UC Davis MIND Institute has found.

Women with preeclampsia experience hypertension during the latter half of their pregnancies, and may have increased levels of protein in their urine and edema, or fluid retention. Preeclampsia can develop into eclampsia, a life-threatening condition in which seizures may occur.

The study was conducted in more than 1,000 children between the ages of 2 and 3 years enrolled in the Childhood Risks of Autism from Genetics and the Environment (CHARGE) study in Northern California. It is published online today in JAMA Pediatrics.

Cheryl Walker, UC Davis

“We found significant associations between preeclampsia and ASD that increased with severity. We also observed a significant association between severe preeclampsia and developmental delay,” said Cheryl Walker, study senior author, assistant professor, Department of Obstetrics and Gynecology Division of Maternal Fetal Medicine and a researcher affiliated with the UC Davis MIND Institute.

While preeclampsia has previously been examined as a risk factor for autism, the literature has been inconsistent. The current study provides a robust population-based, case-controlled examination of the association between autism and preeclampsia and whether risk was associated with preeclampsia severity.

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New genetic links in autism revealed


For answers, UC San Diego researchers turn to mice, stem cells and the ‘tooth fairy.’

Alysson Muotri, UC San Diego

With the help of mouse models, induced pluripotent stem cells (iPSCs) and the “tooth fairy,” researchers at the UC San Diego School of Medicine have implicated a new gene in idiopathic or non-syndromic autism. The gene is associated with Rett syndrome, a syndromic form of autism, suggesting that different types of autism spectrum disorder (ASD) may share similar molecular pathways.

The findings are published in today’s (Nov. 11) online issue of Molecular Psychiatry.

“I see this research as an example of what can be done for cases of non-syndromic autism, which lack a definitive group of identifying symptoms or characteristics,” said principal investigator Alysson Muotri, Ph.D., associate professor in the UC San Diego departments of pediatrics and cellular and molecular medicine. “One can take advantage of genomics to map all mutant genes in the patient and then use their own iPSCs to measure the impact of these mutations in relevant cell types. Moreover, the study of brain cells derived from these iPSCs can reveal potential therapeutic drugs tailored to the individual. It is the rise of personalized medicine for mental/neurological disorders.”

But to effectively exploit iPSCs as a diagnostic tool, Muotri said researchers “need to compare neurons derived from hundreds or thousands of other autistic individuals.” Enter the “Tooth Fairy Project,” in which parents are encouraged to register for a “Fairy Tooth Kit,” which involves sending researchers like Muotri a discarded baby tooth from their autistic child. Scientists extract dental pulp cells from the tooth and differentiate them into iPSC-derived neurons for study.

“There is an interesting story behind every single tooth that arrives in the lab,” said Muotri.

The latest findings, in fact, are the result of Muotri’s first tooth fairy donor. He and colleagues identified a de novo or new disruption in one of the two copies of the TRPC6 gene in iPSC-derived neurons of a non-syndromic autistic child. They confirmed with mouse models that mutations in TRPC6 resulted in altered neuronal development, morphology and function. They also noted that the damaging effects of reduced TRPC6 could be rectified with a treatment of hyperforin, a TRPC6-specific agonist that acts by stimulating the functional TRPC6 in neurons, suggesting a potential drug therapy for some ASD patients.

The researchers also found that MeCP2 levels affect TRPC6 expression. Mutations in the gene MeCP2, which encodes for a protein vital to the normal function of nerve cells, cause Rett syndrome, revealing common pathways among ASD.

“Taken together, these findings suggest that TRPC6 is a novel predisposing gene for ASD that may act in a multiple-hit model,” Muotri said. “This is the first study to use iPSC-derived human neurons to model non-syndromic ASD and illustrate the potential of modeling genetically complex sporadic diseases using such cells.”

For more information on the Tooth Fairy Project, visit http://muotri.ucsd.edu.

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Study: Dozens of genes associated with autism


Functions of newly identified genes converge on a few important biological processes.

Two major genetic studies of autism, led in part by UC San Francisco scientists and involving more than 50 laboratories worldwide, have newly implicated dozens of genes in the disorder. The research shows that rare mutations in these genes affect communication networks in the brain and compromise fundamental biological mechanisms that govern whether, when, and how genes are activated overall.

The two new studies, published in the advance online edition of Nature today (Oct. 29), tied mutations in more than 100 genes to autism. Sixty of these genes met a “high-confidence” threshold indicating that there is a greater than 90 percent chance that mutations in those genes contribute to autism risk.

The majority of the mutations identified in the new studies are de novo (Latin for “afresh”) mutations, meaning they are not present in unaffected parents’ genomes but arise spontaneously in a single sperm or egg cell just prior to conception of a child.

The genes implicated in the new studies fall into three broad classes: they are involved in the formation and function of synapses, which are sites of nerve-cell communication in the brain; they regulate, via a process called transcription, how the instructions in other genes are relayed to the protein-making machinery in cells; and they affect how DNA is wound up and packed into cells in a structure known as chromatin. Because modifications of chromatin structure are known to lead to changes in how genes are expressed, mutations that alter chromatin, like those that affect transcription, would be expected to affect the activity of many genes.

One of the new Nature studies made use of data from the Simons Simplex Collection (SSC), a permanent repository of DNA samples from nearly 3,000 families created by the Simons Foundation Autism Research Initiative. Each SSC family has one child affected with autism, parents unaffected by the disorder and, in a large proportion, unaffected siblings. The second study was conducted under the auspices of the Autism Sequencing Consortium (ASC), an initiative supported by the National Institute of Mental Health that allows scientists from around the world to collaborate on large genomic studies that couldn’t be done by individual labs.

“Before these studies, only 11 autism genes had been identified with high confidence, and we have now more than quadrupled that number,” said Stephan Sanders, Ph.D., assistant professor of psychiatry at UCSF, co-first author on the SSC study, and co-author on the ASC study. Based on recent trends, Sanders estimates that gene discovery will continue at a quickening pace, with as many as 1,000 genes ultimately associated with autism risk.

“There has been a lot of concern that 1,000 genes means 1,000 different treatments, but I think the news is much brighter than that,” said Matthew W. State, M.D., Ph.D., chair and Oberndorf Family Distinguished Professor in Psychiatry at UCSF. State was co-leader of the Nature study focusing on the SSC and a senior participant in the study organized by the ASC, of which he is a co-founder. ”There is already strong evidence that these mutations converge on a much smaller number key biological functions. We now need to focus on these points of convergence to begin to develop novel treatments.”

Autism, which is marked by deficits in social interaction and language development, as well as by repetitive behaviors and restricted interests, is known to have a strong genetic component. But until a few years ago, genomic research had failed to decisively associate individual genes with the disorder.

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Related link:
UC autism summit offers hope for help

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Why are some people with autism hypersensitive to sound?


UC Riverside researchers embark on five-year NIH-funded project.

(From left) Khaleel Razak, Iryna Ethell and Devin Binder. The three researchers are leading a team that will study the mechanisms of auditory hypersensitivity in fragile X syndrome. (Photo by Lille Bose, UC Riverside)

Fragile X syndrome (FXS) is a genetic disorder in humans that causes social impairments and repetitive behaviors, and other behaviors on the autistic spectrum, as well as cognitive deficits. It is the most common inherited cause of intellectual disability and the most common cause of autism.

One aspect of FXS worthy of more research is auditory hypersensitivity – an increased sensitivity to sound through a negative emotional response, resulting in behaviors such as closing the ears with the hands or running away from the sound source. People with FXS also are slow to adapt to constant repetitious sounds in our environment. These hypersensitivity deficits may lead to higher-level auditory deficits such as those involving language.

UC Riverside has received a grant from the National Institutes of Health (NIH) to study the mechanisms of auditory hypersensitivity in FXS from molecules to circuits to therapies.

The five-year $8.7 million grant is awarded to UC Riverside and the University of Texas Southwestern (UTSW) Medical Center, Dallas. UCR will receive approximately $2.7 million of the grant over five years.

NIH recently awarded a total of $35 million to three different centers in the United States to study FXS, allowing the establishment of “Centers for Collaborative Research in FXS.” The UTSW-UCR collaboration is one of the three centers.

The UCR team is being led by Khaleel Razak, an associate professor of psychology; and the School of Medicine’s Iryna Ethell, a professor of biomedical sciences, and Devin Binder, an associate professor of biomedical sciences. The team came together for the project through a collaborative seed grant provided by the Office of Research and Economic Development at UCR and a pilot grant from the FRAXA Research Foundation.

FXS affects 1 in 4,000 boys and is half as prevalent in girls. Symptoms include social and communication deficits, seizures, delayed language development and sensory hypersensitivity.  Despite the prevalence of FXS and the known genetic cause, a cure is yet to be discovered.

“Two recent clinical trials of drugs were suspended because the drugs performed similar to the placebo on outcome measures,” Razak said. “There is, therefore, an urgent need to develop new therapeutic targets and appropriate biomarkers and outcome measures in which the underlying neural mechanism is known at multiple levels of analyses.”

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Moms of kids with autism less likely to take iron supplements while pregnant


First study to examine relationship between maternal iron intake, having a child with autism.

Mothers of children with autism are significantly less likely to report taking iron supplements before and during their pregnancies than the mothers of children who are developing normally, a study by researchers with the UC Davis MIND Institute has found.

Low iron intake was associated with a fivefold greater risk of autism in the child if the mother was 35 or older at the time of the child’s birth or if she suffered from metabolic conditions such as obesity hypertension or diabetes.

The research is the first to examine the relationship between maternal iron intake and having a child with autism spectrum disorder, the authors said. The study, “Maternal intake of supplemental iron and risk for autism spectrum disorders,” is published online in the American Journal of Epidemiology.

Rebecca Schmidt, UC Davis

“The association between lower maternal iron intake and increased ASD risk was strongest during breastfeeding, after adjustment for folic acid intake,” said Rebecca J. Schmidt, assistant professor in the Department of Public Health Sciences and a researcher affiliated with the MIND Institute.

The authors of the current study in 2011 were the first to report associations between supplemental folic acid and reduced risk for autism spectrum disorder, a finding later replicated in larger scale investigations.

“Further, the risk associated with low maternal iron intake was much greater when the mother was also older and had metabolic conditions during her pregnancy.”

The study was conducted in mother-child pairs enrolled in the Northern California-based Childhood Autism Risks from Genetics and the Environment (CHARGE) Study between 2002 and 2009. The participants included mothers of children with autism and mothers of children with typical development.

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