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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Why Does Brain Development Diverge From Normal in Autism Spectrum Disorders?

Disabled World (April 13, 2011)- Rett syndrome, a neurodevelopmental disorder on the autism spectrum, is marked by relatively normal development in infancy followed by a loss of cognitive, social and language skills starting at 12 to 18 months of age. It is increasingly seen as a disorder of synapses, the connections between neurons that together form brain circuits. What hasn't been clear is why children start out developing normally, only to become progressively abnormal. New research from Children's Hospital Boston, published in the April 14 issue of Neuron, helps unravel what's going on.

The researchers, led by Chinfei Chen, M.D., Ph.D., of Children's F.M. Kirby Neurobiology Center, studied synapse development in mice with a mutation in the Mecp2 gene, the same gene linked to human Rett syndrome. They found strong evidence that the loss of functioning Mecp2 prevents synapses and circuits from maturing and refining in response to cues from the environment – just at the time when babies' brains should be maximally receptive to these cues.

Chen believes her findings may have implications not just for Rett syndrome, but for other autism spectrum disorders. "Many ASDs manifest between 1 and 2 years of age, a period when kids are interacting more with the outside world," says Chen. "The brain of an autistic child looks normal, but there's a subtle difference in connections that has to do with how they process experiences. If you could diagnose early enough, there might be a way to alter the course of the disease by modifying experience, such as through intense one-to-one therapy."

Chen and colleagues focused on a synaptic circuit in the brain's visual system that is relatively easy to study, known as the retinogeniculate synapse. It connects the cells receiving input from the eye to the lateral geniculate nucleus, an important relay station in the brain's thalamus. Visual input from the outside world, during a specific "critical period," is crucial for its normal development.

The team tested the functioning of the circuit by stimulating the optic tract and measuring electrical responses in the thalamus to see how the neurons were connected, and how strong the connections were. In Mecp2-mutant mice, these recordings indicated that the visual circuit formed normally at first, and that during the second week of life, weaker connections were pruned away and others strengthened, just as they should be.

But after day 21 of life – after mice open their eyes and when the visual circuitry should be further pruned and strengthened based on visual experience – it became abnormal. The number of inputs and connections actually increased, while the strength of the synapses decreased.

NOTE: To read more about Autism Spectrum Disorders, click on the title above.