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Funding Fears Prevent Researchers from Sharing Mice

January 9, 2012 //
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Larry Reiter studies the chromosomal region 15q11-13, one of the genomic hotspots most firmly linked to autism. At his small lab at the University of Tennessee Health Science Center in Memphis, Reiter has sometimes relied on mutant mice — such as animals missing UBE3A, a key gene in the region — engineered by other groups for his experiments1.

But in the past couple of years, as competition has intensified in autism research, Reiter has had trouble gaining access to new mouse models. Frustrated, he has decided to focus instead on fruit flies.

Reiter says he worries that others might be similarly discouraged. “People will shy away from working in this area, because they can’t get the mouse to work on,” he says.

On paper, most funding organizations, such as the National Institutes of Health (NIH) and SFARI — this website’s parent organization — as well as most scientific journals stipulate that once researchers publish details of a model animal, they must make the animals available to other labs (see list).

“Failure to comply with the sharing plan may be carefully considered in future funding decisions for the investigator and their institution,” says J.P. Kim, director of the Division of Extramural Inventions and Technology Resources within the NIH Office of Extramural Research.

In practice, however, many researchers intentionally delay sharing or don’t share at all.

“It’s sort of the ugly secret,” Reiter says. “There is a long and proud tradition in the mouse field of holding on to your mouse, sometimes for 20 years.”

Read more at…

SFARI, January 2012.

Categories 2012, Autism, Brain Science, Business and Technology, Health and Medicine, News, Politics, SFARI

Gene Hunters Find Cause of Rare Movement Disorder

December 15, 2011 //
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After a challenging two-decade hunt, scientists have pinpointed the gene responsible for a rare disease that causes seizures in infancy and sudden, uncontrollable movements in adolescence and early adulthood.

The findings, published December 15, 2011, in Cell Reports, could pave the way to new therapies for more common forms of seizures and dyskinesias, or abnormal movements, the researchers say.

“There are a lot of dyskinesias for which we don’t have good treatments and they are a big problem, such as in Huntington’s disease and Parkinson’s disease,” says Howard Hughes Medical Institute investigator Louis Ptáček, professor of neurology at the University of California San Francisco, who led the new study. “If we can understand the pathways in the brain that regulate dyskinesia, then it’s my hope that we’ll be able to target better drugs.”

Ptáček’s interest in dyskinesia dates to 1985 when, as a third-year medical student at the University of Wisconsin, Madison, he met a 16-year-old boy who was having bizarre spasms. Every time the boy switched from one movement to another, like from sitting to standing or walking to running, his limbs would inexplicably flail or twist, as if performing an odd dance.”Nobody knew what the heck was going on,” Ptáček recalls.

One night around 2 a.m., after scouring the library’s medical databases, Ptáček figured out the diagnosis: paroxysmal kinesigenic dyskinesia, or PKD, which had been reported in just a handful of other cases. He knew from those papers that PKD could be treated with a low dose of a common anticonvulsant medication. When doctors gave the boy the drug, carbamazepine, he quickly improved.

“He had been having attacks hundreds of times per day. A few weeks after treatment, he was essentially having zero attacks,” Ptáček says. “It felt so satisfying to have gotten it right.”

Read more at…

HHMI News, December 2011.

Categories 2011, Brain Science, Genetics, Health and Medicine, HHMI News, News

Studies of Early Development Reveal Immune Link to Autism

December 15, 2011 //
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The molecular soldiers of the immune system affect brain development and may contribute to many cases of autism. That’s the emerging hypothesis from five new studies that use different methods — ranging from screening blood samples of pregnant women to mathematical analyses of gene expression in the brain — published in the past few months.

One report shows, for example, that pregnant women whose babies later develop autism tend to carry rare antibodies in their blood. Another finds that they harbor an excess of certain signaling molecules of the immune system, called cytokines, in the amniotic fluid. A third study found that some autism risk genes expressed in the developing brain belong to networks of genes related to cytokine signaling.

“These studies further build the case for the relevance of the immune system in autism using totally different approaches,” says Paul Patterson, professor of biology at the California Institute of Technology. Patterson has made animal models of the immune system’s role in brain development but was not involved in any of the new studies.

Many investigations of older children and adults with autism have uncovered signs of the immune system gone awry. The new studies are finding similar signatures in early brain development, from the womb through the first few years of life.

Still, no one knows much about the biological mechanisms that determine when, how or why immune molecules affect the fetal brain — let alone whether or why they might contribute to autism.

“Obviously the immune changes are there and are prominent. We just have to figure out what they’re doing,” Patterson says.

Read more at…

SFARI, December 2011. 

Categories 2011, Autism, Brain Science, Health and Medicine, News, SFARI

Neurons made from stem cells reveal cellular flaws in autism

December 8, 2011 //
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Researchers have uncovered cellular abnormalities in Timothy syndrome by regenerating neurons from individuals with the rare autism-related disorder, according to a study published 27 November in Nature Medicine.

Using a mix of chemicals in a dish, the researchers reprogrammed skin cells from individuals with Timothy syndrome into so-called induced pluripotent stem (iPS) cells and then coaxed these cells to differentiate into neural precursor cells and neurons.

The cells derived from individuals with Timothy syndrome show a host of defects, including abnormal calcium signaling and low numbers of cells that can form long-range connections. Notably, Timothy neurons produce more catecholamines, a class of chemical messengers, compared with neurons reprogrammed from healthy individuals. These chemicals have been linked to autism and, more often, to bipolar disorder and depression.

This chemical excess is largely reversed when researchers expose the cells to a drug called roscovitine, which blocks the flow of calcium across the cell membrane.

The Timothy syndrome gene, CACNA1C, makes a protein needed for a certain type of calcium channel. Mutations in the gene, reported in only a few dozen people, cause heart defects, physical malformations and, usually, autism.

Using the iPS cell approach with rare forms of autism, “you can find things that are interesting potential clinical leads,” says lead investigator Ricardo Dolmetsch, assistant professor of neurobiology at Stanford University in Palo Alto, California. “In a way, it gives you a better preclinical model than we’ve had before.”

Read more at…

SFARI, December 2011.

Categories 2011, Autism, Brain Science, Business and Technology, Genetics, Health and Medicine, News, SFARI

Study Charts Epigenetic Landscape of Autism Brains

December 5, 2011 //
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In the brains of individuals with autism, chemical changes to histones, proteins entwined with DNA, tend to show up near genes linked to the disorder, according to a study of postmortem brains published 7 November in the Archives of General Psychiatry.

In the nucleus of every cell, threads of DNA wrap tightly around spools of histones. Methyl and other chemical groups that attach to either the DNA or histones can turn genes on or off. These so-called epigenetic changes add an extra layer of genetic control by tweaking the amount of RNA and protein produced without changing the underlying DNA sequence.

Looking at postmortem brain tissue from 16 individuals with autism and 10 age-matched controls, the researchers found hundreds of places in the genome where histone methylation is different in individuals with autism.

Many of these abnormal epigenetic marks land on or near known autism risk genes, suggesting that the biological pathways involving these genes may be important even in children with autism who do not carry mutations in the genes, the researchers say.

“You could say that the epigenetic risk architecture that’s described is tracking the genetic risk architecture,” says lead investigator Schahram Akbarian, professor of psychiatry at the University of Massachusetts Medical School.

Read more at…

SFARI, December 2011.

Categories 2011, Autism, Brain Science, Genetics, Health and Medicine, News, SFARI

Tuberous Sclerosis, Fragile X May Be Molecular Opposites

December 1, 2011 //
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Some forms of autism are caused by too many proteins at the synapse, the junction between neurons, whereas other forms result from too few, according to a study published 23 November inNature.

The findings suggest that drugs that effectively treat people with one form of autism may not help, and may even harm, individuals with another form, the researchers say.

“One implication is, boy, it’s going to be important to know where you are on this spectrum to devise the right therapy,” says lead investigator Mark Bear, professor of neuroscience at the Massachusetts Institute of Technology.

The work, first presented at the 2010 Society for Neuroscience annual meeting in San Diego, focuses on mouse models of two genetic diseases: fragile X syndrome, the most common inherited cause of autism, and tuberous sclerosis complex (TSC), characterized by benign tumors, seizures and, often, autism.

Autism is notoriously diverse. But the new study suggests that many forms of the disorder stem from a spectrum of disruptions to the same biological pathway, Bear says. “The hope is we’re gaining insights that will be broadly applicable.”

Read more at…

SFARI, December 2011.

Categories 2011, Autism, Brain Science, Genetics, Health and Medicine, News, SFARI

Motor Problems Key Feature in Autism, Family Study Suggests

November 21, 2011 //
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In families that have at least one child with autism, significant motor impairments crop up in most children with the disorder and hardly any of their unaffected siblings, according to a study published 19 October in Autism.

Many studies have shown motor problems in people with autism, but this is the first to investigate whether family members also have them. Motor deficits such as clumsiness, poor muscle tone and difficulty with fine and gross motor skills crop up in some 80 percent of children with the disorder, but are not part of the diagnostic criteria.

Because motor problems consistently accompany autism in families, they should be considered part of the disorder, the researchers say.

“We know there are many ways to get to autism,” says lead investigator John Constantino, professor of psychiatry and pediatrics at Washington University in St. Louis. “What we’re saying is that it looks like many of them may be associated with motor coordination deficits, at a level that rivals the frequency of communicative or language deficits.”

Read more at…

SFARI, November 2011.

Categories 2011, Autism, Brain Science, Health and Medicine, News, SFARI

Researchers Unveil Seven New Rat Models of Autism

November 16, 2011 //
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Sigma Life Science, a St. Louis-based research company, debuted seven new rat models of autism Tuesday evening at the 2011 Society for Neuroscience annual meeting in Washington, D.C.

Six of the rats each lack one autism candidate gene — FMR1, NLGN3, MeCP2, NRXN1, CACNA1C and PTEN — and a seventh lacks mGluR5, which encodes a neuronal signaling receptor that is important in fragile X syndrome.

The impetus for making the rat models is to make autism research more attractive to the pharmaceutical industry. The standard approach in the industry is to test dosage and toxicology in rats, not in mice.

“Unless there’s investment, it doesn’t matter how many great ideas — which tend to be risky — you generate, they will not proceed forward,” says Robert Ring, vice president of translational research at the advocacy organization Autism Speaks. The idea is not to replace mice, Ring adds, but “to begin creating complementary animal models that help facilitate translational research.”

Over the past few months, Richard Paylor at Baylor College of Medicine in Houston, Texas, has done behavioral testing on young rats missing FMR1 — mutations in which lead to fragile X syndrome — and NLGN3, one of the first genes implicated in non-syndromic autism.

Unexpectedly, some of the rat behaviors are the opposite of what’s seen in their mouse counterparts: The FMR1-deficient rats engage in social play less than controls do, for example, whereas some strains of mice lacking FMR1 have more social interactions than controls.

Rats missing either FMR1 or NLGN3 also show some unexpected new characteristics, such as severe female aggression and compulsive chewing on water bottles.

Read more at…

SFARI, November 2011.

Categories 2011, Autism, Brain Science, Conference Coverage, Genetics, Health and Medicine, News, SFARI, SfN

Vision Problems in Rett Could Serve as Biomarker

November 13, 2011 //
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Mice missing the Rett syndrome gene MeCP2 show a gradual decline in vision, and too much inhibitory signaling in the visual cortex, according to unpublished research presented Thursday at Cell Symposia: Autism Spectrum Disorders: From Mechanisms to Therapies in Washington, D.C., a satellite conference of the Society for Neuroscience annual meeting. Normalizing the balance of excitatory and inhibitory signals restores the animals’ sight, the researchers report.

This abnormality in the visual area of the brain could be one of the first steps in a developmental cascade in the mice and, perhaps, in people with Rett syndrome, the researchers say.

Preliminary research in girls with Rett suggests that clinical trials for the syndrome could track visual sharpness, or acuity, in the participants to assess a drug’s effectiveness, says Takao Hensch, professor of molecular and cellular biology at Harvard University. Hensch was presenting work led by Michela Fagiolini of Children’s Hospital Boston.

“This is a totally objective, quantifiable measure,” Hensch says. “This could be a biomarker that would indicate the efficacy of any type of treatment.”

Read more at…

SFARI, November 2011.

Categories 2011, Autism, Brain Science, Conference Coverage, Health and Medicine, News, SFARI, SfN
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