Without research, there are no miracles and no hope.

Blog written by Christine Matthews

We all brag about our children on FB from academic achievements, to proms, graduations, and sporting events, but we don’t get to post those things about Casey.

See we live in a world where Casey is regarded by some as a retard, and sometimes unfortunately, as a freak, or as a young man who will never amount to much. I am thankful that he seems unaware of the brutality of this reality.

But yesterday’s MRI changed how some very important people view him. No Casey did not became an All-Star, or make honor roll, or recite the words we so long to hear him speak. Yesterday my friends Casey became a TRAILBLAZER. See this MRI was for the brilliant men and women the MD’s, PhD’s, & Researchers at The Mount Sinai Medical Center who are desperately seeking answers with regards to the autism epidemic.

They needed him. They needed his mind.
You see without investigation/research there are no cures, no miracles, and no hope.

The information they gather is not expected to help Casey, but what we do passionately believe is that future generations will have a life with perhaps fewer challenges and possibly less heartache then we have had to endure.

Remember NOT all superheroes wear capes.

Can viral infection in expecting mothers lead to neurodevelopmental disorders?

ASF funded fellow Nick Goeden from USC examines the role of the placenta.  

Blog written by Priyanka Shah, ASF intern 

Many researchers are studying various factors during pregnancy that can lead to an increased risk of autism and other neurodevelopmental disorders in children. Maternal infection and inflammation have been shown to be risk factors for autism and schizophrenia. For example, in recent news, we have seen how expecting mothers infected with the Zika virus have given birth to babies with a high-risk for brain damage and other abnormalities. So, studying how maternal health (in this case, a viral infection) affects the fetus can help us predict for possible disorders and possibly even prevent them.

Nick Goeden, graduate student and lead researcher

In particular, at the University of Southern California, Nick Goeden and colleagues studied how the placenta was affected after the mother experienced inflammation. The placenta is a tissue in a woman’s uterus that provides nourishment to the fetus through the umbilical cord. The placenta also produces an important chemical messenger, called serotonin, which is transmitted to the fetus and plays a role in organizing the brain during development. After birth, it helps regulate emotions and has been implicated in depression and anxiety.

Researchers decided to use a mouse model to see how maternal inflammation can affect the production of serotonin in the placenta and brain development in the fetus. To do this, they used a chemical that induces inflammation in pregnant mice, and mimics flu-like conditions seen in humans. They found that the amount of serotonin in the placenta drastically increased, leading to increased amounts of serotonin in the fetal brain. During brain development, brain cells migrate and become connected together like an electric network. The formation of certain brain cells that specifically help move serotonin around was disrupted, which means that the fetus’ brain became wired differently. Because of this, some of the behaviors serotonin helps control could have been affected. And in fact, other studies have shown how maternal infection during pregnancy can lead to increased anxiety or depression-like symptoms in the offspring.

This study shows that even mild inflammation during pregnancy can induce a series of events that eventually disrupts the development of the fetal brain. Although these children will have a higher risk for known mental disorders such as ASD or schizophrenia, these diagnoses are not guaranteed. Our next steps in this line of research should be to see the long-term effects of inflammation on the serotonin-specific brain cells and related behaviors. Researchers should also look at how other infections and viruses might be changing the production of other chemical messengers or molecules in the placenta. Understanding the biological mechanisms of the placenta and of fetal brain development can help direct new research into prevention and therapy for neurodevelopmental disorders in children.

A new way to look at the brains of males and females with autism

Sex differences are found in the brains of people with autism in particular regions

Though autism spectrum disorder (ASD) is diagnosed more frequently in boys than in girls, experts do not understand why. There is some evidence that gender differences exist, but more needs to be done to understand specifically what is happening at the cellular and network levels. So few brains of people with autism are available for study that this has been a very hard question to answer – but with the progress of the Autism BrainNet (www.takesbrains.org), this is becoming a possibility.

Boryana Stamova, PhD, lead researcher

Researchers at UC Davis, led by Boryana Stamova and colleagues, focused on understanding non-coding RNA molecules (sncRNA, including miRNA), which are parts of the genome that control gene activity, rather than “coding” for new proteins. New studies are showing that these “non-coding,” non-protein forming RNA molecules are as important as “coding, protein forming” RNA molecules for brain development. Moreover, selected non-coding RNA can target and regulate multiple “coding” molecules in different regions of the brain.

This study looked at these molecules in two areas of the brain known to be involved in autism. First, the superior temporal sulcus (STS) association cortex which participates in circuits necessary for understanding social cues and facial expressions. Secondly, the primary auditory cortex, which is involved in sound processing. They looked at 5,000 sncRNAs in brains of people with ASD and compared them to the brains of people without autism. The sncRNA that were studied included those involved in cell to cell signaling, axon guidance, and formation of synapse which affect the core autism deficits. The goal was to see if there are different patterns of the sncRNAs between male and female brains with ASD.   As expected, the sncRNA expression was different between those with autism and those without autism. In addition, there were differences of sncRNA in brains of males and females with autism including those that affect the axon guidance pathway.

Could this explain why females have different symptoms, or that they may be able to mask their symptoms through more adaptive social abilities? There is much more work that needs to be done. Unfortunately there are so few brains of people with autism, and even fewer brains of females with autism, that this question has been hard to study.

You can make a difference in understanding the brains of people with autism. Even if you do not have autism yourself, you can register with the Autism BrainNet to learn more about post-mortem donation. There is no obligation.  You receive a quarterly newsletter that provides important information, scientific discoveries, and resources for the community. It’s easy, go to www.takesbrains.org.

Where are the genes that control sex differences in autism?

…they aren’t where you would think.  ASF fellow Dr. Donna Werling from UCSF explains.

Dr. Donna Werling studies sex differences in autism at UCSF

Males are approximately 4 times more likely to be diagnosed with autism spectrum disorder (ASD) than girls and women^1,2, and for the most part, scientists don’t know why. To figure out how sex differences in human biology might contribute to ASD risk, we compared patterns of gene expression from males and females in the developing and adult human brain. We found that genes that show higher expression levels in males relative to females include many of the same genes that are expressed at higher levels in the brains of individuals with autism relative to controls³. What these male-elevated and ASD-elevated genes do in the brain may be a clue to the sex difference in ASD prevalence.

A closer look at these genes showed that they are known to be involved in the functions of microglia and astrocytes. Microglia are a type of cell involved in the immune system of the brain, and astrocytes are different type of cell that provides support to neurons that communicate across regions of the brain. Our findings suggest that these non-neuronal cell types may play a role in the biology behind the male-biased risk for ASD and may provide insight on why more males are diagnosed compared to females.

How did we do this? It involved lots of time and access to valuable resources.

In order to understand the role of different cell types in the brain, we needed to study actual brain tissue from people. In order to do this, we turned to a project called BrainSpan⁴, a publicly available data set generated from post-mortem human samples from the brains of males and females. Brain tissue is an incredibly rare resource and this dataset is invaluable in our research. Using these data from BrainSpan, we generated a list of genes that have different expression levels in males and females in the adult cerebral cortex and we used this list to look at two questions relating to autism:

Our first question was “Do genes that are directly associated with autism risk differ between males and females?” For example, the genes CHD8 and TSC1 which are both known to contribute to the cause of ASD^5,6. If these genes show up differently in males and females, then mutations in these genes would affect male and female brains differently, which might lead to the sex differences we see in ASD diagnoses. In fact, we found this was not the case: genes directly associated with autism risk do not show up differently in males and females.

Our second question was “Do genes that are indirectly associated with autism differ between the sexes?” For our study, we considered genes that show changes in expression level in the ASD brain to be indirectly associated with autism^7,8. This includes genes that show low expression in the ASD brain; these genes may be affected by directly associated ASD risk genes from our first question. This also includes genes that show high expression in the ASD brain; these genes are related to the brain’s immune system. If these indirectly associated genes with altered expression in the ASD brain are expressed differently in males and females, this would suggest that autism and sex-differential biology affect some of the same molecular or cellular pathways in the brain. These shared pathways may modulate the impact of risk factors such that males are more strongly affected. In contrast to our first question, we found that several of the indirectly ASD associated gene sets did overlap significantly with sex-differentially expressed genes. Specifically, gene sets with coordinated, elevated expression in the ASD brain overlap with genes with higher expression in males, and these overlapping genes are associated with microglia and astrocytes.

These results suggest that, instead of directly affecting ASD risk genes, sex-differential biology interacts with ASD risk biology downstream from these ASD risk genes, and that this interaction may involve the functions of microglia and/or astrocytes.

We repeated our experiment and replicated our results in two additional data sets, including one data set from prenatal brain samples. This is especially important because midfetal development is a key time for the expression, and presumably function, of directly associated ASD risk genes^10,11. Therefore, the patterns that we see demonstrate that not only do microglial and astrocyte genes differ by sex in the adult brain, but they also differ in the same region and time window of development when ASD risk genes are robustly expressed..

That microglia and astrocytes may be involved in sex differences in ASD is intriguing, since these types of cells are becoming more and more recognized for their roles in neural circuitry development by supporting the formation, maintenance, and/or pruning of synapses^12,13. Therefore, sex differences in the functions of these cell types could lead to differences in neuroanatomy and function between males and females. Supporting this idea, studies in rodent models show that the numbers of microglia that take up residence in the brain during early development differ between males and females¹⁴, and also that astrocytes in the hypothalamus express estrogen receptors and change morphology in response to estradiol exposure¹⁵. However, it is not currently known whether these phenomena also occur in humans.

Since microglial and astrocyte genes and cells function downstream from currently known ASD risk genes, treatments that mimic these specific processes could potentially help large numbers of patients with diverse genetic backgrounds. However, several key questions remain. First, our results must be replicated in larger data sets, preferably including comparable numbers of typically developing and autistic males and females. This will be necessary to corroborate the patterns we see and to more directly investigate the interacting effects of sex and ASD on gene expression. The only way we can do this is with more brain tissue from people with autism, which is why the Autism BrainNet is so important for the community. Further research will also be required to determine why microglial and astrocyte genes differ in males and females, and to clarify exactly how sexually dimorphic microglia and/or astrocytes function in the brain to influence neurodevelopment and ASD risk.

Eventually, a major goal will be to translate these findings into tangible benefits for individuals with ASD and their families, perhaps by developing therapeutics that target functional pathways at the intersection between sexually dimorphic and autistic biology. By implicating ASD-upregulated microglial and astrocyte genes at this intersection, our study has uncovered an intriguing new avenue to pursue in our endeavor to fully understand ASD and the striking sex difference in its prevalence.

We gratefully acknowledge the data resources of the BrainSpan consortium, as well as the generous donations from individuals and families that make such invaluable data sets possible. I also acknowledge my co-authors on this study, Dr. Daniel Geschwind and Dr. Neelroop Parikshak, our funding from the US National Institute of Mental Health (5R37MH060233 and 5R01MH094714 to DHG; Autism Center for Excellence network grant 9R01MH100027; F30MH099886 and T32MH073526 to NNP; F31MH093086 to DMW), and Dr. Stephan Sanders and Dr. Alycia Halladay for their input on this post. Finally, I would like to thank the Autism Science Foundation for the opportunity to share this work with the community.

 

References

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