Researchers Unveil Seven New Rat Models of Autism

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.

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SFARI, November 2011.

Normocentric World

Here at SFARI.org, most of the researchers we write about, whether geneticists, neuroscientists or clinicians, are trying to understand the intricacies of the autistic mind — and some, ultimately, are trying to ‘normalize’ it.

Laurent Mottron, professor of psychiatry at the University of Montreal in Canada, has long argued against this notion of ‘normal.’

As he wrote in a Nature commentary earlier this month, Mottron believes that “autism should be described and investigated as a variant within the human species,” not as a defect to be suppressed.

His argument reminds me of a popular psychological test called the Strength Deployment Inventory, or SDI, that companies often use to train managers. The test is based on the premise that an individual’s weaknesses are merely misplaced strengths. Arrogance is misplaced confidence, according to this logic, an indecisive individual is one who is flexible, and a gullible person is often trusting.

The same dual perspective can be applied to autism. People who don’t have autism — or, as Mottron calls them, “normocentric” — often describe the features of autism as deficits: delayed, obsessive, narrowly focused, socially awkward, uncommunicative.

But some of these traits can, in the right circumstances, be advantageous. An obsessive person might be passionate, and one who’s narrowly focused probably has exceptional attention to detail.

Mottron argues that the normocentric attitude is pervasive in the scientific literature of autism, and he has a point. For example, he points out that some brain imaging studies find that people with autism have abnormally thick cortical layers, whereas others find them abnormally thin, but in either case, the findings are called deficits. And many autism papers end with a paragraph about how the data could help treat the disorder.

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SFARI, November 2011.

Optogenetics Method Moves into Monkeys

Researchers can delay a monkey’s reaching movement by shining a beam of light into its brain, according to unpublished research presented at a poster session Sunday at the 2011 Society for Neuroscience annual meeting in Washington, D.C.

Researchers have used the technique, called optogenetics, to manipulate several brain circuits in mice, including those that control movement, anxiety and social interactions.

Because people are more similar to monkeys than to mice, the primate version of this flashy technique will be invaluable for understanding which circuits underlie human behaviors, the researchers say. It could eventually lead to treatments for motor or psychiatric disease, akin to deep brain stimulation, they add.

“As optogenetics becomes more viable as a therapeutic tool in the future, we’re beginning the process of validating safety and efficacy in non-human primates,” says Dan O’Shea, a graduate student inKrishna Shenoy‘s lab at Stanford University, who showed the poster.

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SFARI, November 2011.

Vision Problems in Rett Could Serve as Biomarker

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.”

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SFARI, November 2011.

Autism Brains Have Too Many Neurons, Study Suggests

Children with autism have an abnormally large number of neurons in the prefrontal cortex (PFC), a brain region important for abstract thinking, planning and social behaviors, according to a study published yesterday in the Journal of the American Medical Association.

Because of the study’s small sample size, however, and the complexities of analyzing postmortem brains, many researchers caution against interpreting the results as relevant for all children with autism.

In the study, researchers analyzed postmortem brain tissue from two areas of the PFC from seven boys with autism and six controls, ranging in age from 2 to 16 years. In the brains from the children with autism, the dorsolateral PFC, which comprises the outer layers of the region, holds 79 percent more neurons, and the mesial PFC, encompassing deeper tissue, holds 29 percent more neurons compared with controls, the study found.

According to lead investigator Eric Courchesne, the study provides a cellular explanation for imaging studies showing brain overgrowth in children with the disorder.

“Now for first time, in my opinion, there’s a fairly robust and specific pathology that can be used in animal model studies and cellular studies to test speculations about genetic and non-genetic factors that could cause this disorder,” says Courchesne, professor of neurosciences at the University of California, San Diego.

Other experts are skeptical of the results, however, saying they may not represent the wider population of children with autism.

“I would emphasize that this study is very preliminary. Only seven individuals with autism were included and it’s just one region,” says Nicholas Lange, associate professor of psychiatry and biostatistics at Harvard University, who wrote a commentary of the study in the same issue of the journal.

“My overwhelming feeling is that not too much should be made of this at this point,” says David Amaral, director of research at the University of California, Davis MIND Institute. “It would be premature to draw any conclusions until the study has had an independent replication using a much larger number of brains.”

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SFARI, November 2011.

A Raw Nerve

At a walkathon one Saturday in September, nearly 5,000 people traced two miles of Chicago’s lakefront to raise money for research into the progressive nerve disease that is thought to have killed baseball star Lou Gehrig. Janice Caliendo was there collecting blood samples from friends of those affected by the incurable disease to be used as controls in future genetic studies. Caliendo, a lab manager at Northwestern Memorial Hospital in the Streeterville neighborhood of the city, often attends these sorts of fundraisers, but this time she was getting more attention than usual.

Her lab, headed by Northwestern University neurologist Teepu Siddique, has been all over the news recently for a study published in August in Naturereporting a new gene associated with the disease formally known as amyotrophic lateral sclerosis (ALS). “Breakthrough could lead to effective treatment for Lou Gehrig’s disease,” read the LA Times‘s headline; “Cause of ALS is found, Northwestern team says,” wrote theChicago Tribune. In honor of the study, in fact, the event’s organizers asked Siddique to lead the walkathon. Countless people approached Caliendo that day with the same questions: Does this mean there’s a cure? Is there a blood test for ALS? Is there a drug to treat it?

The answer to all these inquiries was ‘no’. “It’s not a cure, but people read into it what they want to hear,” Caliendo says. “I don’t think they were disappointed, though, because it’s still very good news. It’s huge.”

[…]

Chinese Survey Says…

Here in the United States, psychologists have been talking about autism since Leo Kanner’s first description of the disorder in 1943. But in China, the first case wasn’t reported until 1982.

It’s perhaps not surprising, then, that knowledge of autism in China is still pretty spotty. According to a large survey published last month, just 58 percent of people in China can identify characteristic features of autism from multiple choices.

The researchers analyzed responses from a survey of 4,947 parents or caregivers of kindergarteners in Harbin, one of China’s largest cities. The survey asked multiple-choice questions about the disorder such as ‘What are the symptoms of autism?’ and ‘Do you think that autism is a rare disease?’ It also asked them what they would do if their child showed symptoms of the disorder.

Based on the responses, 94 percent had heard of autism, but many had gaps in their knowledge and held interesting misconceptions. Most correctly identified that autism affects communication, language and eye contact. Only 45.9 percent knew that it is also often accompanied by narrow interests and stereotyped behaviors, and only 36.7 percent recognized that children with autism may talk to themselves or talk repetitively. Two-thirds of respondents answered ‘No’ when asked, ‘Do you think that the onset of autism is only in childhood?’

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SFARI, November 2011.

Bilingualism Doesn’t Hinder Language

Growing up bilingual doesn’t impair language skills in children with autism, according to two studies in the Journal of Autism and Developmental Disorders.

For the first half of the 20th century, many scientists believed that learning more than one language impairs a child’s cognitive development. That idea has been debunked in the past few decades, but for children with autism, some clinicians still recommend learning only one language.

The two new studies, the first to rigorously investigate this issue, challenge that idea.

The first, published 22 September, studied 75 children with autism, between 3 and 6 years of age, separated into three groups: 30 who were monolingual, 24 who were exposed to a second language before 12 months of age, and 21 who were exposed to a second language after 12 months of age.

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SFARI, November 2011.

Young Brains

If you’re a neuroscientist hoping to do experiments on brain tissue from children with autism, you have a steep road ahead of you: Existing brain banks hold samples from just 1,300 young brains, including only a few hundred from children with the disorder.

Research on postmortem brains, particularly young brains, is messy — biologically, politically and ethically. But the tissue provides a unique window into how autism takes shape in the developing human brain — bringing researchers many steps closer to the problem than genetic blood tests, brain imaging studies or psychological experiments.

Last week, an editorial in Nature called on government and nonprofit organizations to push for an international tissue bank of brains from tens of thousands of children and fetuses, either healthy or with any of various brain disorders.

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SFARI, November 2011.

Size of 22q13 Deletion Predicts Clinical Features

In a study of people missing an autism-linked region on chromosome 22, researchers have found that the larger the deletion, the more likely the individual is to have severe symptoms, from motor and speech delays to a large head and fleshy hands.

The study, published 7 October in the Journal of Medical Genetics, analyzed individuals with the rare Phelan-McDermid syndrome, caused by deletions of various sizes in the chromosomal region 22q13. The syndrome is characterized by a wide array of symptoms, often including autism or some traits of the disorder.

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SFARI, November 2011.