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Summary of Advances Cover 2011

Summary of Advances

In Autism Spectrum Disorder Research


Question 2: How Can I Understand What Is Happening?

Mutations causing syndromic autism define an axis of synaptic pathophysiology – Auerbach BD, Osterweil EK, Bear MF. Nature. 2011 Nov 23;480(7375):63-8. [PMID: 22113615]

New research reveals that two genetic forms of autism, fragile X syndrome and tuberous sclerosis, are actually caused by opposite malfunctions – while fragile X is caused by overproduction of proteins at the synapse, tuberous sclerosis is caused by underproduction. Interestingly, while the causes of fragile X and tuberous sclerosis are distinctly different, both disorders often result in intellectual disability and autism spectrum disorder. Researchers made the discovery while studying mGluR5 (Metabotropic glutamate receptor 5), a receptor on the surface of neurons that is key in aiding communication at the synapse – the junction between neurons. During normal signaling, the mGluR5 receptor binds to the neurotransmitter glutamate after it is released across the synapse, resulting in the production of new synaptic proteins. Fragile X protein (FMRP) halts protein synthesis to ensure that the appropriate amount is produced – in fragile X syndrome, changes to the gene that controls FMRP allow synaptic proteins to continue production unchecked, resulting in too much protein. Researchers have previously shown that introducing a substance to block mGluR5 reverses some of the symptoms of fragile X, and human drug trials are currently underway. Armed with an understanding of the underlying causes of fragile X, researchers in this study examined mice with tuberous sclerosis mutations and discovered something surprising. In this case, the disorder was caused by the opposite malfunction – too little protein synthesis at the synapse, which could be treated with a drug stimulating mGluR5. Further, when the researchers bred the two mice together, many of their autistic features went away. The findings of the study indicate that proper brain function can only occur within a narrow range of mGluR5 protein synthesis – changes in either direction lead to syndromes with similar behavioral symptoms. This also suggests that drug treatments for autism spectrum disorder will need to be individually tailored, as conditions that appear similar may have quite different underlying causes.

Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits – Peñagarikano O, Abrahams BS, Herman EI, Winden KD, Gdalyahu A, Dong H, Sonnenblick LI, Gruver R, Almajano J, Bragin A, Golshani P, Trachtenberg JT, Peles E, Geschwind DH. Cell. 2011 Sep 30;147(1):235-46. [PMID: 21962519]

A new mouse model of autism, created by eliminating a gene strongly associated with the disorder in humans, shows promise for understanding the biology that underlies ASD and testing new treatments. By eliminating the CNTNAP2 gene (contactin associated protein-like 2), researchers were able to create mice with behaviors that closely mimicked those of its human counterparts – the mice exhibited repetitive behaviors, abnormal social interactions, and irregular vocalizations, in addition to experiencing seizures and hyperactivity. CNTNAP2 is thought to play an important role in the development of language, and variants of the gene have been linked to an increased risk of autism and epilepsy. Prior to experiencing seizures, the mice showed signs of abnormal brain circuit development – researchers observed irregularities in communication between neurons and their migration within the brain. These observations complement earlier studies suggesting that children with autism carrying a CNTNAP2 variant have a "disjointed brain." The frontal lobe is poorly connected with the rest of the brain but shows an overconnection with itself, resulting in poor communication with other brain regions. Notably, the mice in the study responded positively to risperidone, an antipsychotic medication approved by the FDA to treat symptoms of irritability and aggression associated with ASD. While their social interactions did not improve – risperidone has not been shown to improve social function in humans – there was a marked improvement in repetitive grooming and a decrease in hyperactivity. Creating an animal model of autism that closely resembles the symptoms and behaviors in humans may be an important tool in understanding neural development in autism and developing new treatments.

Protein interactome reveals converging molecular pathways – Sakai Y, Shaw CA, Dawson BC, Dugas DV, Al-Mohtaseb Z, Hill DE, Zoghbi HY. Sci. Transl. Med. 2011 Jun 8;3(86):86ra49. [PMID: 21653829]

A recent study sheds light on how a variety of different mutations in genes that seemingly have little in common can each result in the symptoms of autism. To answer this question, researchers developed a molecular map of protein networks or "interactome" to identify how proteins associated with ASD interact with hundreds of other proteins. Researchers used genes known to be associated with syndromic autism as a starting point for building the interactome. Syndromic autism occurs as part of a broader genetic disorder such as fragile X, Angelman syndrome, and Rett syndrome – understanding protein interactions with syndromic autism may give insight into idiopathic autism, or autism with no known cause. Using 26 genes associated with syndromic autism, researchers hypothesized that the seemingly dissimilar genes might interact with shared partners in common molecular pathways, leading to the symptoms of autism. Indeed, researchers identified a complex network of 539 proteins that interacted with the autism-related proteins, successfully demonstrating that all of the proteins linked to autism are connected by interactions with common partners. The interactome confirmed previously suspected gene relationships and several new pairings, such as the connection between SHANK3 and TSC1, which share 21 common protein partners. Researchers then performed a microarray analysis on 288 individuals with idiopathic autism in a search for genes within the interactome. They identified three novel copy number variations – chromosomal deletions and duplications – on genes found in the network, demonstrating that the interactome may help to identify new genes related to ASD and understand complicated genetic variation.

Transcriptomic analysis of autistic brain reveals convergent molecular pathways – Voineagu I, Wang X, Johnston P, Lowe JK, Tian Y, Horvath S, Mill J, Cantor RM, Blencowe BJ, Geschwind DH. Nature. 2011 May 25;474(7351):380-4. [PMID: 21614001]

A study found surprising consistency in molecular changes seen in the brains of people with autism across the spectrum, suggesting a common biological basis that may span multiple subtypes. Researchers analyzed postmortem brain tissue and found atypical patterns of gene expression common to many of the individuals with ASD. These findings may provide clues about how autism changes the brain at the molecular level, and lead to new avenues for developing treatments. In the study researchers focused on gene expression – the way information from the gene is used in the synthesis of functional gene products, often proteins. These proteins then perform specific tasks in the cell. In brains affected by autism, genes involved in neuron function and communication were expressed at much lower levels than in typically developing individuals, and the expression of genes involved in certain immune functions was abnormally high. The authors note that many of these genes are active during fetal development, supporting the theory that abnormal brain development may start very early in the womb. The findings also provide evidence that molecular changes in neuron function and communication are probably a cause of autism, rather than a result of the disorder. To identify common patterns of gene expression among people with autism, the researchers compared the frontal and temporal lobes of the brain – the frontal lobe is responsible for higher-level thinking including judgment and social response, while the temporal lobe plays a key role in hearing and language and is also involved in sensory integration. They found that more than 500 genes were expressed at different levels in the frontal and temporal lobes of typically developing individuals, as would be expected in separate brain regions with differing functions. However, there was almost no difference in the levels of gene expression between the two regions in the brains of those with ASD. This blurring suggests a failure to differentiate regions in early brain development.

Question 2

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