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publicado em 20/06/2011 às 03h00:00
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Scientists create new mouse model for study of autism

Tests reveal the mechanism by which mutations affect brain and behavior to evoke disorder like autism in mice

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Researchers at Johns Hopkins University, USA, developed a new mouse model that mimics a human genetic mutation associated with autism spectrum disorders.

Experiments with mice have revealed a molecular mechanism by which mutations SHANK3 affect the brain and behavior to evoke a disorder similar to autism in mice.

Scientists have identified the protein SHANK studies in synaptic proteins that are regulated by neuronal activity. They said they were motivated to develop a mouse model after other studies showed that a subset of children with autism carrying mutations SHANK3. Patients with a mutation that prevented SHANK3 to form complexes in the synapse had a particularly severe disease, despite having one mutant and one normal copy of SHANK3.

To refine a mouse model of disease that mimic the human mutation, the researchers altered a copy of SHANK3 and left an intact copy of the normal gene.

"We hope that our model of accelerated protein degradation is applicable to other genetic causes of autism and possibly schizophrenia," said researcher Paul Worley. "Behavioral changes in these mice can be understood as a result of changes in synaptic proteins."

The student Ali Bangash, along with Worley, used biochemical methods to assess levels and activity of protein SHANK3 in sections of the mutant mouse brain. He found that the amount of normal protein SHANK3 was drastically reduced in mice with mutant SHANK3. In addition, the mutant protein SHANK3 seemed to make the normal protein SHANK3 become targets for rapid degradation. In fact, the amount of SHANK3 that makes its way up the synapses in the brain is reduced by 90% compared with normal mice.

"By modifying a copy of SHANK3, we do not just lose half the amount of protein that would normally be produced, we lose more good protein," Worley said, adding that the team also looked at behavioral and electrophysiological changes when a modified copy of SHANK3 in mice.

In one experiment, the researchers electrically stimulated nerve cells in the rat brain, assessed the strength of synapses SHANK3 mutants and compared them to normal brain tissue, mice without mutations.

The scientists found that the proportion of two different types of proteins vital to memory and learning was amiss in SHANK3 mutants.

Comparative study

The team also evaluated the behaviors of the mutants using SHANK3 social interaction tests and comparing them to normal mice. In one test, a mutant SHANK3 was placed with another rat in a cage, leaving them free to explore. The mouse mutant SHANK3 spent much time away from society. The wild type showed an increased level of interest, indicated by time sniffing the SHANK3 mutant. However, when the mutant SHANK3 was allowed to leave freely, while the other rat was confined under a dome with cracks, the mutant mouse with SHANK3 showed greater interest by exploiting the mouse detained more than a normal type did under similar circumstances. The researchers say this behavior is consistent with the characteristics of a disorder such as autism.

In another test, a young rat was introduced to three times a SHANK3 mutant mouse and a normal type. Both the mouse and the normal type of mutant mouse SHANK3 spent less time exploring the young rat in each successive interaction, indicating that they have become accustomed to each other.

When a different mouse, the same age and genetic inheritance was introduced in the test, the mouse type normal animals re-explored with renewed interest, apparently recognizing it as "new." The mutant SHANK3, also apparently recognizing it as new, not only re-explored, but became markedly aggressive, nipping and biting a mouse, a behavior that the researchers also concluded that resembled autism.

   Palavras-chave:   Autism    Mouse model    Johns Hopkins University    Paul Worley   
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