La risorsa globale per le prove scientifiche sulla sperimentazione animale

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Autism

Autism is a range of conditions collectively known as autism spectrum in social situations when needing to interpret signs of communication between people. Although this is often the case, there is a great range of symptoms across people with autism and these can change over time, making it difficult to define autism or systematically diagnose it.

Autism was first defined in 1943, yet researchers were slow to get a better understanding of the disorder. For many years it was incorrectly believed that emotionally distant mothers were the cause. Even in the mid-1990s it was thought to occur in only 1 in 2500 people. Diagnosed cases of autism have risen sharply over the past 20 years, with 1 in 88 children now diagnosed with autism in the US. This has led to a similarly dramatic increase in the amount of research into the condition.

The varied nature of autism spectrum disorders means that it is unlikely there will be a single cause or cure. It is only by building a repertoire of potential causes that researchers can develop treatments for individual cases.

Mice are an important part of this research as they can model certain aspects of the condition. Researchers study the mice to examine the effects of treatments on the mice's behaviour including sociability, repetitive behaviour and restricted interests. This research has led to several discoveries of potential causes of autism and allowed work to begin on finding treatments.

Genetics
Chloride ions
Bacteria
Inflammation
References

Genetics

Mice are important models for autism research and the development of potential treatments
It is known that over 50% of cases can be attributed to a genetic causeANCHOR. This means that there is great hope for research into different genes that could trigger autism. Genes such as ShankANCHOR, PTEN and SLC6A4 have been linked to autism through studies in mice.

Other genes have a direct cause for autistic conditions. For example, Rett syndrome is caused by a mutation in the MeCP2 gene. This disease primarily affects girls, as the gene is on the X chromosome and boys with the mutation often die shortly after birth as they do not have a second copy of the gene like girls. The syndrome can be replicated in genetically modified mice, who suffer from similar symptoms to their human counterparts, such as shortened lifespan, breathing difficulties and behavioural dysfunctionANCHOR. Through the use of this mouse model, several treatments are currently in development for reducing the impact of these symptomsANCHOR ANCHOR ANCHOR ANCHOR ANCHOR ANCHOR ANCHOR ANCHOR.

Chloride ions

A study of two rodent models of autism in 2013 suggested that higher levels of chloride ions in the brain could be a factor in autismANCHOR. Chloride ions are used by nerves to pass signals to each other. The level of these ions in neurons normally drops after birth, which is triggered by a hormone called oxytocin. This calms the neurons and appears to help babies deal with the stress of birth. In the rodent models of autism, these chloride levels did not fall and EEG tests showed that brain activity was not under control.

The mice and rats were then given bumetanide, a common drug for high blood pressure that blocks chloride channels in neurons by boosting the effect of the neurotransmitter GABA. This was able to restore chloride levels and brain activity to normal and there were improvements in social behaviours. A clinical trial of bumetanide in children with severe autism has shown improvement to their social interactions and it is hoped that further research can build on thisANCHOR.

Bacteria

It also appears that the bacteria in the body can have an effect on the body’s chemistryANCHOR. Mice raised with completely no exposure to bacteria have altered brain chemistry and show autistic traits. This could be linked to changes in the amount of GABA and how the brain responds to it. The bacterium Lactobacillus rhamnosus, which is used in dairy products, produces GABA and alters production of GABA receptors in mice, which results in decreased anxiety15ANCHOR. For another mouse model of autism, the bacterium Bacteroides fragilis improves the behavioural traits and gastro-intestinal problems in young miceANCHOR.

Inflammation

Another factor linked to autism is inflammation. Although it is a natural part of the body’s protection, too much can be a bad thing. Experiments that have aimed to reduce inflammation in people with autism have shown success. This is despite their rather unusual methods including taking hot baths and swallowing thousands of whipworm eggs. These have both stemmed from anecdotal evidence but are now heading towards clinical trials.

A more severe approach is a bone marrow transplant. Research has suggested that infection in pregnant mothers can lead to an imbalance in the offspring’s immune system, leading to inflammationANCHOR,ANCHOR. Bone marrow transplants in these offspring in mice have been shown to alleviate some of the autism-like behaviourANCHOR. A procedure like this for autism patients would be too dangerous and have serious side-effects, but it is hoped that this research will lead to a treatment that can mimic the beneficial effects.


References

  1. Ronald A et al (2006) J Am Acad Child Add Psy 45,691-699
  2. Peça J et al (2011) Shank3 mutant mice display autistic-like behaviours and striatal dysfunction Nature 472, 437–442 doi:10.1038/nature09965
  3. Katz DM et al (2012) Preclinical research in Rett syndrome: setting the foundation for translational success Dis Model Mech. 5(6):733–745 doi: 10.1242/dmm.011007
  4. Abdala AP et al (2010) Correction of respiratory disorders in a mouse model of Rett syndrome Proc Natl Acad Sci USA 107(42):18208-13
  5. Deogracias R et al (2012) Fingolimod, a sphingosine-1 phosphate receptor modulator, increases BDNF levels and improves symptoms of a mouse model of Rett syndrome. Proc Natl Acad Sci USA. 109(35):14230-5
  6. Guy J et al (2007) Reversal of neurological defects in a mouse model of Rett syndrome Science 23;315(5815):1143-7
  7. Kron M et al (2012) Brain activity mapping in Mecp2 mutant mice reveals functional deficits in forebrain circuits, including key nodes in the default mode network, that are reversed with ketamine treatment. J Neurosci 32(40):13860-72
  8. Nag N, Berger-Sweeney JE (2007) Postnatal dietary choline supplementation alters behavior in a mouse model of Rett syndrome. Neurobiol Dis. 26(2):473-80
  9. Roux JC et al (2007) Treatment with desipramine improves breathing and survival in a mouse model for Rett syndrome. Eur J Neurosci. 25(7):1915-22
  10. Schmid DA et al (2012) A TrkB small molecule partial agonist rescues TrkB phosphorylation deficits and improves respiratory function in a mouse model of Rett syndrome. J Neurosci. 32(5):1803-10
  11. Tropea D et al (2009) Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice. Proc Natl Acad Sci USA. 106(6):2029-34
  12. Tyzio R et al (2014) Oxytocin-Mediated GABA Inhibition During Delivery Attenuates Autism Pathogenesis in Rodent Offspring Science 343(6171):675-679 doi:10.1126/science.1247190
  13. http://news.sciencemag.org/brain-behavior/2012/12/diuretic-drug-offers-latest-hope-autism-treatment
  14. http://www.newscientist.com/article/mg22129530.400-psychobiotics-how-gut-bacteria-mess-with-your-mind.html
  15. Bravo JA et al (2011) Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci USA 108(38):16050-5 doi:10.1073/pnas.1102999108
  16. Hsiao EY et al (2013) Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders Cell 19;155(7):1451-63 doi:10.1016/j.cell.2013.11.024
  17. Mostafa GA et al (2010) Frequency of CD4+CD25high Regulatory T Cells in the Peripheral Blood of Egyptian Children With Autism J. Child Neurol. 25, 328-335 doi:10.1177/0883073809339393
  18. Atladóttir HO et al (2010) Maternal Infection Requiring Hospitalization During Pregnancy and Autism Spectrum Disorders J. Autism Dev. Disord. 40, 1423-1430 doi:10.1007/s10803-010-1006-y
  19. Hsiao EY et al (2012) Modeling an autism risk factor in mice leads to permanent immune dysregulation Proc. Natl. Acad. Sci. USA 109, 12776-81 doi:10.1073/pnas.1202556109

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