Guest blogger & TACA Physician Advisory: Dr. Richard Frye
Dr Courchesne of the University of California at San Diego, a researcher who has previously published groundbreaking papers on abnormalities in the growth of the brain in children with autism, now provides new insight into previous uncovered brain abnormalities in children with autism in a recent publication in the New England Journal of Medicine (Stoner et al., 2014). Previously Dr Courchesne has provided important insight into the abnormalities in brain development related to autism. His group has nicely explained some of the origins of the abnormal increased in brain size found in some children with autism and has provided insight into the abnormal structure of cell in the cerebral cortex of children with autism. Now his group describes some of the additional reasons behind why neurons in the cerebral cortex are not functioning as they should in children with autism.
Dr Courchesne determined whether 63 genes were turned on or turned off in several important areas of the cerebral cortex in 11 children with autism spectrum disorder and compared these measurements to the brains of children of similar age and gender that developed normally. The areas of the cortex that were examined included the posterior superior temporal cortex, which is a key area for processing language, and the occipital cortex, which is a key area for processing vision, but the great majority of the samples were derived from the dorsolateral prefrontal cortex, which is a key area of the brain responsible for working memory, planning, behavioral regulation and reasoning. The researchers performed a very detailed analysis of very thin slices of brain tissue so the different layers of the cerebral cortex could be examined in detail.
Overall, these researchers found that the genes that they examined were appropriately working in all but one child from the control group. However, 10 of the 11 children with autism were found to have patches of about 5-7mm (about a quarter inch) in length that extended through several layers of the cortex in which specific genes where abnormally turned off and not working. These patches occurred in the majority of the samples from the dorsolateral prefrontal cortex (91% of samples) and posterior superior temporal cortex (100% of samples) but not in of the occipital cortex (0%). The areas of the brain that were found to have abnormal patches are the same areas of the brain believed not to function correctly in many individuals with autism.
Of course what is important is the reason why these genes were not working. If there were something wrong with the genetic code resulting in the genes not working, then these genes would not be working throughout the brain not just in certain patches in the brain or in specific areas of the brain. In recent years we have started to learn about how genes are turned on and off without altering the genetic code. This process is called epigenetics and is very important in understanding why the brain and body does not work in individuals with autism spectrum disorder. Many lines of research have demonstrated that genes are abnormality turned off and on in individual with autism. What we are starting to learn is that many physiological abnormalities associated with autism such as oxidative stress, mitochondrial dysfunction and inflammation can result in epigenetic changes in gene expression. In a recent review article authored by Dr Rossignol and myself (Rossignol and Frye, 2014; http://journal.frontiersin.org/Journal/10.3389/fphys.2014.00150/abstract) we point out that these physiological processes that can alter gene expression are located in these critical portion of the brain, thus potentially explaining some of the findings from Dr Courchesne’s study.
Some of the limitations of this study include the fact that the brain samples were from proportionally more individuals with autism who were non-verbal and had intellectual disability than the general autism population as well as the relatively small number of samples examined. Hopefully further work can investigate the reasons for these changes in gene expression in the brain, why such changes occur in only certain areas of the brain, when these changes start and what can be done to treat or prevent such changes from occurring.
Stoner R, Chow ML, Boyle MP, Sunkin SM, Mouton PR, Roy S, Wynshaw-Boris A,
Colamarino SA, Lein ES, Courchesne E. Patches of disorganization in the neocortex of children with autism. N Engl J Med. 2014; 370:1209-19. doi: 10.1056/NEJMoa1307491.
Rossignol D and Frye RE (2014). Evidence linking oxidative stress, mitochondrial dysfunction and inflammation in the brain of individuals with autism. Front. Physiol. 2014; 5:150. doi: 10.3389/fphys.2014.00150
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