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Two new autism mouse models highlight gene dosage effects

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Virginia Hughes
6 October 2011

Varying volumes: Eight brain regions (colored) are significantly larger in mice carrying a deletion of chromosomal region 16p11.2 than in those with a duplication of the region.

Two new genetic mouse models that debuted this week show that having too many or too few copies of certain genetic regions leads to an array of symptoms reminiscent of autism.

A study published yesterday in Science Translational Medicine found that mice carrying three copies of the autism candidate gene UBE3A have repetitive grooming behaviors, fewer vocalizations and little interest in social interactions1. UBE3A is located in chromosomal region 15q11-13, the most common place in the genome for genetic causes of autism.

This came on the heels of another report, published 3 October in the Proceedings of the National Academy of Sciences, on another much-talked-about region, 16p11.2. The researchers showed that mice carrying only one copy of this region have severe repetitive behaviors, larger-than-normal volumes of many brain regions and tend to die young. By contrast, those with three copies have low motor activity, smaller-than-normal volumes of the same brain areas and are relatively healthy2. These data were first presented at a Boston symposium in December.

Deletions of this segment, informally known as 16p, crop up in roughly one percent of individuals with autism. Duplications also show up in a few people with autism and, more commonly, in people with schizophrenia.

Both papers highlight what is sometimes called the 'Goldilocks phenomenon' of gene dosage, notes Jeremy Veenstra-VanderWeele, assistant professor of psychiatry, pediatrics and pharmacology at Vanderbilt University in Nashville, Tennessee, who was not involved in either study. "You can have too little and end up with a problem in brain development or synaptic function, or you can have too much and end up with same sort of problem."

The new mice are useful because "we don't know where the boundaries of these 'genetic disorders' really are," he says.

Three versus two:

Researchers first linked the 15q11-13 region to autism in 19913. An estimated one to three percent of individuals with autism carry duplications of this large segment, encompassing at least 30 genes and almost always inherited from the mother.

Researchers have investigated several genes in this region, but the most famous is UBE3A. The loss of this gene causes Angelman syndrome, characterized by developmental delay, seizures, impaired speech and, intriguingly, a cheerful demeanor.

"This was previously called 'happy puppet syndrome,' which describes the propensity for these kids with Angelman to smile a lot, to laugh a lot and to be hypersocial," says Matthew Anderson, director of neuropathology at Beth Israel Deaconess Medical Center in Boston and lead investigator of the new UBE3A study. "It seemed to be diametrically opposite of what an autistic individual would present as."

Individuals typically inherit two copies of each chromosome, one from the mother and one from the father. Some genetic regions within these chromosomes, such as the 15q11-13 segment, are imprinted, meaning that one of the copies is silenced.

So far, two groups have made mice carrying duplications of the entire 15q11-13 region. Others have tinkered with genes within it, including UBE3A and receptors for the neurotransmitter GABA, or gamma-aminobutyric acid4.

The new study reports the first mice carrying duplications of just the UBE3A gene, which is located within 15q11-13. The researchers engineered the mice to express either two or three copies of the gene — one or two more than normal, respectively.

Animals with three copies fail several social interaction tests, spending an equal amount of time with other mice and novel objects, whereas mice with two copies prefer to be social. Unlike healthy mice and those with two extra copies of UBE3A, those with three copies do not emit ultrasonic vocalizations in the presence of other mice.

Finally, mice with three copies of the gene show dramatic repetitive behavior in the form of excessive self-grooming, whereas those with two copies are no different than normal animals.

Unlike some other autism mouse models, these mutants showed no problems with anxiety, motor function, memory or smell. The findings suggest that UBE3A has a major role in social behavior. "It seems to be fairly limited as far as what things it impairs," Anderson says.

Agnostic approach:

In the second new study, Alea Mills and colleagues created mice carrying either deletions or duplications of 16p11.2, which contains 27 genes. The direct comparison of these mice is important because copy number variations of this segment have been linked to a wide variety of disorders and are sometimes seen in healthy people.

Normal mice (top, right) gradually explore all areas of the ceiling, whereas mice carrying a 16p deletion (top, left) explore only one part. Above, lines showing the paths of each animal.

"We tried to do side-by-side [comparisons] for everything," says Mills, professor of genetics at Cold Spring Harbor Laboratory in New York. For every test, she says, she found that "it's much worse to have too few than too many copies of this region."

In fact, she found that half of the animals carrying the deletion die just after birth. If what they find in mice extends to humans, she says, the findings suggest that 16p11.2 deletions may cause infant mortality.

Behaviors of the mice with the deletion or duplication are often reciprocal. For example, mice with a deletion are extremely hyperactive, whereas those with a duplication are relatively lethargic. Mice with a deletion slept little, mimicking what many parents report about their children with autism, and those with a duplication slept more than normal, Mills says.

Perhaps most strikingly, the mice carrying deletions repetitively climbed across the ceiling of their cages. "The duplication mice didn't like to crawl on the ceiling at all," she says.

Some experts praise Mills' study for its unusual approach to measuring behavior. The researchers used a sophisticated infrared camera system called HomeCageScan that tracks the precise movements of the mice for up to two weeks.

"We can't interpret mouse behavior easily," notes Veenstra-VanderWeele. The ceiling climbing behavior, for example, is "the sort of thing you wouldn't necessarily pick up unless you took this agnostic approach."

Still, the drawback of this method is that because the behaviors haven't been validated on more standardized tests, it's difficult to interpret them.

"It sounds like these guys were like Spiderman, stuck on the ceiling," notes Andrew Holmes, chief of the Laboratory for Behavioral and Genomic Neuroscience at the National Institute on Alcohol Abuse and Alcoholism. "It's a very interesting observation that would have led me to do more formal established tests for repetitive behavior."

Brain measures:

Perhaps the most important contribution of these new studies is that they analyzed not only behavior, but alterations in the brain.

In the UBE3A study, the researchers showed that in the barrel cortex — the area of the mouse brain that processes sensory information from whiskers — mice carrying three copies of UBE3A have dampened transmission of glutamate. This neurotransmitter is important for excitatory signaling and has been linked to autism.

"It's really interesting to see this signaling pathway coming up again and again," says Holmes, whose mouse model of Williams syndrome also points to glutamate.

Using magnetic resonance imaging, the 16p study found that mice carrying deletions in the region have larger volumes of eight brain regions compared with controls.

"They used neuroimaging as a way to link behavioral abnormalities to what actually appears to be changed in the brain," Veenstra-VanderWeele says. "That's not been done in a lot of mouse models so far."

These are only the latest two in a barrage of new mouse models of autism. In 2011 alone, researchers have described mice carrying glitches in the Timothy syndrome gene CACNA1C, SHANK3 and, just last week, CNTNAP2.

"The point of making these mice is that we can study what's happening in the brain at a very fundamental mechanistic level," says Ed Cook, professor of psychiatry at the University of Illinois College of Medicine in Chicago. "Now, with multiple models, we can start working on common mechanisms."


1: Smith S.E.P. et al. Sci. Transl. Med. Epub ahead of print (2011) Abstract

2: Horev G. et al. Proc. Natl. Acad. Sci. Epub ahead of print (2011) Abstract

3: Gillberg C. et al. J. Am. Acad. Child Adolesc. Psychiatry 30, 489-494 (1991) PubMed

4: DeLorey T.M. et al. J. Neurosci. 18, 8505-8514 (1998) PubMed


Name: whatever
6 October 2011 - 3:36PM

Dude, it is still a mystery as to what "causes" autism. We know it is genetic. After that, we know nothing. Mice are nothing like humans, autism is not a "disease", your experiment did not meet the SM, and "autism like symptoms" are not the same as autism.

Name: RAJensen
7 October 2011 - 2:29PM

'Whatever' brings up several important points. The SFARI model that autism is a heritable genetic disorder does not distinguish between the concepts of 'genetics' and 'inheritance'. The four genetic syndromes mentioned in the article Angelman Syndrome, Timothy Syndrome, 16P microdeletion and microduplication Syndromes and Williams Syndrome simply do not fit the SFARI genetic heritable model. Almost all genetic and epigenetic cases of Angelmans Syndrome, Williams Syndrome and Timothy Syndrome are caused by de novo mutations,reproductive errors (egg or sperm),in sharp contrast to being inherited events, and the mutation is not present in either parent. Most cases of 16P syndormes are also caused by reproductive errors (egg or sperm). When transgenerational inheritance does occur, the parent(s) are always unaffected as far as autism is concerned.

The ambiguity of autism is another important confounder for the SFARI inherited genetic model. Angelman Syndrome is associated with developmental delay, speech impairments, seizures and severe gross motor impairments.

The Angelmans Syndrome foundation is a collaborative foundation whose members are comprised of parents, families, therapists and the worlds leading research authorities on Angelman Syndrome in the world. If you visit their web site they state unequivically that Angelman Syndrome is often misdiagnosed as cerebral palsy or autism:


Name: Virginia Hughes
7 October 2011 - 3:14PM


Thanks, as always, for reading SFARI.org and for commenting. In my opinion, the overlap of symptoms among autism and these various syndromes is one of the most interesting, and mysterious, aspects of the disorder.

There really isn't a "SFARI model." We choose stories for SFARI.org based on what's coming out in the scientific literature and discussed at conferences. We try to cover a wide variety of fields, including genetics, molecular biology, cognition and behavior, and are not trying to promote any particular genetic theory.

Name: RAJensen
10 October 2011 - 8:09PM


As far as the Simons funded study of 16P11.2 mutations is concerned do you know if the study will be recording a comprehensive medical history of the participating families.

I ask that because there are genes within the 16p11.2 region that are associated with risk for juvenile renal disease (FJHN) and sytemic lupus erythematosus (TGAM). Systemic lupus erythematosus is also associated with risk in Klinefelter Syndrome a genetic disorder also associated with autism risk.

Immune deficiences and auto-immune diseases are associated with autism risk.





Name: John Spiro
12 October 2011 - 3:08AM

A comprehensive medical history will indeed by taken for individuals participating in the Simons Variation in Individuals Project (Simons VIP), the study of deletions and duplications of 16p11.2 referred to above.

Name: RAJensen
16 October 2011 - 4:19PM

The knock out mice studies says nothing about the mechanisms that cause the behaviors. Three of the genetic deletion syndromes associated with specific genetic regions also harbor genes that regulate the immune system which is also associated with autism risk. The KO mouse models include KO mice that have deleted regions of interest including 7q11.23 (Williams Syndrome), 16p11.2 (16p deletion syndrome) and 22q11.21 (DeGeorge Syndrome).

The deletions of these regions in mice include deleting genes that regulate the immune system. When these regions are deleted the mice have had their immune systems destroyed. It should be an important strategy to determine if the KO mice have immune deficiencies that may cause the behaviors and if so it would open a new line of translational research, developing novel therapies that would stabilize or repair the damaged immune systems before the symptoms begin to emerge.


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