Hyperconnectivity In Brain's Hearing Center Caused By Gene Mutation In Autism

Medical News Today (Feb. 2, 2012)-New research from Cold Spring Harbor Laboratory (CSHL) might help explain how a gene mutation found in some autistic individuals leads to difficulties in processing auditory cues and paying spatial attention to sound.

The study has found that when a suspected autism gene called PTEN is deleted from auditory cortical neurons - the main workhorses of the brain's sound-processing center - the signals that these neurons receive from local as well as long-distance sources are strengthened beyond normal levels. These effects, the study shows, can be blocked by a drug currently in use as an immunosuppressant.

"It's long been hypothesized that autism spectrum disorders (ASDs) arise from a partial disruption of long-range connections in the brain during development," explains Professor Tony Zador, who led the study. "Our finding that PTEN-deficient neurons receive stronger inputs suggests that one way this disruption can be caused is by signal enhancement." His team's work appears in the Journal of Neuroscience.

Although ASDs could arise from mutations in any of dozens of candidate genes, a core triad of symptoms defines all cases: impaired language, impaired social interaction, and restricted and repetitive behaviors. "The challenge therefore has been to understand how this diverse set of candidate genes and the pathways they control converge to cause the common signature of ASDs," Zador says.

The auditory cortex, which plays a critical role in auditory attention and perception, forms functional connections with other sensory cortices and critical brain areas. The neural network within the auditory cortex has therefore been a target of studies aimed at understanding how alterations in neural circuits contribute to dysfunction in ASDs.

Zador's team focused for several reasons on the role of one suspected autism candidate gene, PTEN, on circuit alterations within the auditory cortex. Well known for its role as an anti-cancer gene that powers down cell growth, proliferation and survival, this gene has also been linked to ASDs by a slew of studies in humans and mice. PTEN mutations have been found in autistic individuals with extreme macroencephaly - an increase in brain volume. PTEN loss in mice has been found to boost cell size and the number of neuronal connections in the brain.

To decipher the role of PTEN on functional connectivity in the auditory cortex, Zador's group selectively disrupted the function of the PTEN gene in adult mice, only in a subset of neurons of the auditory cortex, while leaving the gene intact in neighboring neurons. The scientists then assessed the effect of the loss of PTEN on connectivity within the auditory cortex using techniques that involve stimulation by laser or flashes of blue light to trigger neuronal activity either locally or in other brain areas that send neuronal projections into the auditory cortex.
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One More Step Towards the End of Recessive Diseases

Genetic Future (Jan. 20, 2011)- "In the last century infant mortality has declined precipitously in the Western world, thanks in large part to the development of antibiotics and vaccination. Yet as the suffering and death from infectious disease has reduced, the burden from genetic disease has become proportionately greater: currently around 20% of all infant deaths in developed countries are a result of inherited Mendelian (single-gene) disorders.

What can be done to reduce this burden? Increasingly sophisticated methods for detecting disease in embryos during pregnancy will help, and these have recently taken another step forward with the development of accurate, non-invasive methods based on analysing foetal DNA in the blood of pregnant mothers (an article in the BMJ this week demonstrates the feasibility of this approach for a non-Mendelian disease, Down syndrome; and the same group showed late last year that this approach can also be applied to effectively any known disease-causing mutation). Yet these approaches detect disease after pregnancy has already begun.

Disease mutations can also be detected in embryos prior to implantation, for prospective parents undergoing IVF. But IVF remains an expensive, arduous and invasive procedure, and thus a weapon of last resort for most parents-in-waiting; as Armand Leroi notes drily in an exceptional 2006 article in EMBO Reports: “nature has contrived a cheap, easy and enjoyable way to conceive a child; IVF is none of these things.” (While Leroi goes on to argue that the challenges of IVF are less severe for young couples with no fertility problems, it still seems fairly implausible that this will become the default mode of reproduction in the near future.)

However, for some classes of Mendelian disease it’s possible to move the screening one step back. Recessive diseases are insidious things. The mutations that cause them lurk undetected – each of us carry perhaps 5 to 10 of them – as their carriers are protected by the presence of a healthy second copy of the affected gene. These mutations can thus wait silently for generation after generation, until a carrier is unlucky enough to fall for someone who carries the same mutation, or another mutation in the same gene. The children of such a couple will each have a 25% chance of inheriting one damaged copy of the gene from each parent and thus developing the disease."

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