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News

New mouse model mimics many symptoms of autism

by  /  3 October 2011
High fidelity: Compared with controls (left), mice lacking CNTNAP2 (right) have fewer interneurons, which dampen electrical signaling in the brain.

High fidelity: Compared with controls (left), mice lacking CNTNAP2 (right) have fewer interneurons, which dampen electrical signaling in the brain.

Mice lacking the autism-related gene CNTNAP2 also show brain circuit disruptions similar to those seen in people who carry mutations in the gene, the study found.

What’s more, risperidone, a drug often used to treat the symptoms of autism, ameliorates some behaviors, including hyperactivity and repetitive behavior, in these mice.

The researchers presented an early look at the behavioral findings at the 2011 International Meeting for Autism Research.

The study is clearly a landmark in autism research and cause for optimism, says Nicholas Gaiano, associate professor of neurology at Johns Hopkins University School of Medicine in Baltimore, who was not involved with the work.

“Not only does the work further cement a role for CNTNAP2 in autism biology from a behavioral standpoint, but it provides a beautiful example of how disruption of an [autism]-associated gene can profoundly disrupt brain development,” Gaiano says.

Mutations in CNTNAP2 are associated with a higher risk of autism2,3. People who have inheritedmutations in both copies of the gene have a rare disorder called cortical dysplasia-focal epilepsy syndrome, or CDFE. The syndrome is characterized by epileptic seizures, loss of language, intellectual disability and, in some 70 percent of cases, autism.

Some genetic variants of CNTNAP2 are also associated with specific language impairment, a disorder not accompanied by intellectual disability, autism or physical problems such as hearing loss.

The faithfulness with which the new model recapitulates many of the features of autism came as a surprise to the investigators.

“I thought it would be a great system for studying how this gene affects neural development,” says lead investigator Daniel Geschwind, chair of human genetics at the University of California, Los Angeles School of Medicine.

The mice offer that and much more: They are hyperactive, have social and vocal communication deficits and repetitive behavior, all hallmarks of autism.

“I’ve been somewhat conservative about making parallels between human behavior and mouse behavior,” says Geschwind. “I’m much more optimistic about using mice after seeing this.”

Signaling imbalance:

 

Like people with CDFE, mice lacking both copies of CNTNAP2 develop seizures. The mutants also have fewer interneurons — a subtype of neurons that dampen electrical signaling in the brain.

Specifically, the mice have fewer neurons that produce a signaling molecule called gamma-aminobutyric acid or GABA, which slows down neural activity. This suggests that the loss of CNTNAP2 disrupts the balance between excitatory and inhibitory signaling in the brain.

The brains of the mutant mice also reveal aberrations in neuronal migration: Rather than traveling to their proper destinations, neurons cluster in clumps or rows in the deep layers of the cortex. About 43 percent of individuals with CDFE show visible evidence of these defects on magnetic resonance imaging scans, Geschwind says.

The defects in interneurons and in neuronal migration may underlie the circuit abnormalities seen in the animals, Geschwind says. But it’s not yet clear whether these defects are caused by the same molecular mechanism, or occur independently of each other.

In either case, the end result is lack of synchrony in signaling through synapses, the junctions between neurons, in the mutant animals. This defect may affect a diverse set of pathways, leading to the range of behavioral symptoms seen in the animals.

“The real power of this analysis is that [Geschwind] has not just looked at the cellular and synaptic level, but begun to point out how broad pathways are affected,” says Gordon Fishell, professor of developmental genetics at New York University’s Langone Medical Center.

The emerging picture is not just a snapshot, Fishell says. “It’s a landscape that offers a holistic picture of how autism is manifested at a biochemical level in the brain.”

The new findings build on five years of investigation, which began when Brett Abrahams, a former postdoctoral fellow in Geschwind’s lab, used microarrays to analyze gene expression in human fetal brains.

That work identified CNTNAP2 as a gene that showed a peculiar pattern of enrichment in the prefrontal cortex that wasn’t seen in mice or rats, says Abrahams, now assistant professor of genetics at the Albert Einstein College of Medicine in New York City.

At first, the researchers linked variants in the gene with language, but not with autism.

Israeli researcher Elior Peles developed the mutant mice and carried out studies of the peripheral nervous system in the mice.

In 2010,a functional magnetic resonance imaging study led by Geschwind’s lab showed that unaffected children who carry a common variant of CNTNAP2 show the same aberrant pattern of brain connectivity as do children with autism4.

“It’s a really nice story from the laboratory research perspective,” says Geschwind. “It shows how convergent approaches point you in the right direction.”

The new model also holds promise for developing treatments for autism. Risperidone ameliorates some autism-associated behaviors in the animals, but it has no effect on their social deficits. It is likely that two or three drugs combined with behavior therapy will be necessary to treat the disorder, Geschwind says.


References:
  1. Peñagarikano O. et al. Cell 147, 235-246 (2011) Article
  2. Arking D.E. et al. Am. J. Hum. Genet. 82, 160-164 (2008) PubMed
  3. Alarcón M. et al. Am. J. Hum. Genet. 82, 150-159 (2008) PubMed
  4. Scott-Van Zeeland A.A. et al. Sci. Transl. Med. 2, 56ra80 PubMed
  • RAJensen

    As a contrarian, I would point out that a CNTNAP2 – (neurexin–neuroligin) axis has been associated in two genetic syndromes with high rates of of severe autistic symptoms, Klinefelter Syndrome and Pitt-Hopkins Syndrome. All cases of Klinefelter Syndrome and almost all cases of Pitt-Hopkins syndrome are caused by de novo mutations in contrast to being inherited events. The question that has to asked is where is the heritability in the genetic syndromes with high rates of severe autistic symptoms. These findings are consistent with the Rutter hypothesis which states that genes underlying the broader autism phenotype may not be the same as the genetic (Downs Syndrome) and environmental factors (congenital rubella syndrome) involved in the disruption of early brain development and the transition to the handicapping disorder.

    Common polymorphisms in the CNTNAP2 gene and FOXP2 gene which both reside in the 7q35 region have been associated with autism risk, however that association is secondary to the more robust association with a wide array of mild autistic-like features and disease in general population studies including obsessive compulsive disorder, variability in spoken language, diabetic nephropathy, auto-immune synaptic disorders, dyslexia, selective mutism and social-anxiety related traits and Tourette’s Syndrome. In knockout mice all of these mild autistic-like traits would be severely expressed.

    REFERENCES
    http://ghr.nlm.nih.gov/condition/pitt-hopkins-syndrome
    http://ghr.nlm.nih.gov/condition/klinefelter-syndrome
    Verkerk et al (2003). CNTNAP2 is disrupted in a family with Gilles de la Tourette Syndrome and obsessive compulsive disorder. Genomics 2003 Jul;82(1):1-9.
    Alarcon et al (2005). Quantitative genome scan and Ordered-Subsets analysis endophenotypes support language QTL’s. Mol Psychiatry 2005 Aug;10(8);747-57.
    Bishop & Scerif (2011). Klinefelter Syndrome as a window on the etiology of language and communication impairments in children: the neurologin-neurexin hypothesis. Acta Paediatr 2011 Jun;100(6):903-7.
    Conway et al (2004). Association between in the actin-binding gene caldesmon and diabetic nephropathy in type 1 diabetes. Diabetes 2004 Apr;53(4):1162-5.
    Peter B et al (2011). Replication of CNTNAP2 association with nonword repetition and support for FOXP2 association with timed reading and motor activities in a dyslexia family sample. J Neurodev Disord 2011;Mar;3(1);39-49.
    Serratrice G & Serra trice J (2011). Continuous muscle activity, Morvan’s Syndrome and limbic encephalitis:ionic or non-ionic disorders?. Acta Myol 2011;Jun;30(1);32-3.
    Stein et al (2011). A common genetic variant in the neurexin super family member CNTNAP2 is associated with increased risk for selective mutism and social-anxiety related traits. Biol Psychiatry 2011;May 1;69(9):825-31.

  • Shree Vaidya

    Yes, this is a land mark in autism research.Thanks to those who are devoted to the research work.If the autism is one of the causes due to neuron disorder, the disordered neuron can be modulated,rsonated and also be detected and then filtered out for further analysis,I think.Thank you.

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