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Dr. Daniel Messinger, University of Miami

Last year, a study in Molecular Autism published by the Baby Siblings Research Consortium, or BSRC, led by Dr. Daniel Messinger at the University of Miami, examined characteristics of male and female siblings of those with an autism spectrum disorder. These younger siblings have a 20 fold increased probability of an autism diagnosis themselves. Because of this, they are the perfect group for studying early signs and symptoms of autism, biological markers before behavioral features emerge, and risk factors.   Around 20% of the time they will develop autism, 20% of the time they show symptoms of developmental problems but not ASD, and the rest are on a normal trajectory by 36 months1, therefore this is also the perfect group to study the female protective effect. This protective effect, if it exists, is most likely to be seen in the siblings of individuals with autism, and if there is something protecting females against an autism diagnosis, possibly the female sisters is the place to start looking.

A previous study in the general population looking at the co-occurrence of symptoms in twins observed female protection through what is known as the Carter Effect. The Carter Effect is defined by the higher incidence of a disorder in relatives when the person affected is the least commonly affected by sex. In other words, since females are less commonly affected, the Carter Effect was seen in the twin of a female with autism. If the co-twin did not have autism, autism symptoms were likely to be higher if they had a sister with autism compared to a brother.2

The BSRC study on the infant siblings looked for the Carter Effect in the infant siblings by looking at ASD diagnosis, scores on instruments like the Mullen (which tests IQ in younger kids) or severity scores of autism behaviors.   They did not find that the sex of the person with autism had any effect on these variables in the sibling, and therefore did not observe the Carter Effect.

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Dr. John Constantino, Washington University School of Medicine

But that does not mean a protective effect was not there. When John Constantino from Washington University in St. Louis (who is also involved in infant sibling research) took a look at the data, he found evidence of a protective effect. Despite the absence of the Carter effect, there remains a very substantial male/female difference in ASD diagnosis.3 As it turns out, while there were equal numbers of male and female siblings in the study, boys were three times more likely to be diagnosed with autism than girls. In this sample where there is a high genetic liability of autism, there is a higher probability of boys to be diagnosed with autism vs. girls. This is not the first time the nature of the female protective effect has been seen in this way. Dr. Constantino has also shown a protective effect for females in other cohorts in which the absence of the Carter effect was simultaneously observed: these include the AGRE and IAN cohorts.4-7

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The female protective effect can be seen in the difference between the two arrows

The original BSRC paper also found higher Mullen scores and lower autism repetitive symptoms in high-risk girls, mirroring other studies8,9. This may contribute to a protective effect which explains some of the reason why fewer females are diagnosed. There area also questions around the age of onset of symptoms, male bias in diagnostic instruments, and social perceptions of male and female specific behaviors. However, this protective effect, if it can be defined and described biologically, may lead to treatments and prevention of debilitating symptoms seen in both males and females.

The healthy and productive debate and conversation on this issue is exactly the sort of scientific conversations that move scientific discovery forward.   Not squabbling or one-upping one another, but carefully and thoughtfully discussing these ideas on an open forum for even others to comment on.   If this had not happened, these new insights would never have been shared with the community. Thank you to the editors of the journal Molecular Autism, Simon Baron-Cohen and Joseph Buxbaum, as well as BSRC and to Dr. John Constantino for making sure this happened.v4

 

References:

  1. Messinger D, Young GS, Ozonoff S, et al. Beyond autism: a baby siblings research consortium study of high-risk children at three years of age. Journal of the American Academy of Child and Adolescent Psychiatry. 2013;52(3):300-308 e301.
  2. Robinson EB, Lichtenstein P, Anckarsater H, Happe F, Ronald A. Examining and interpreting the female protective effect against autistic behavior. Proceedings of the National Academy of Sciences of the United States of America. 2013;110(13):5258-5262.
  3. Constantino JN. Data from the Baby Siblings Research Consortium confirm and specify the nature of the female protective effect in autism: A commentary on Messinger et al. Molecular autism. 2016;7:32.
  4. Goin-Kochel RP, Abbacchi A, Constantino JN, Autism Genetic Resource Exchange C. Lack of evidence for increased genetic loading for autism among families of affected females: a replication from family history data in two large samples. Autism : the international journal of research and practice. 2007;11(3):279-286.
  5. Constantino JN, Charman T. Diagnosis of autism spectrum disorder: reconciling the syndrome, its diverse origins, and variation in expression. The Lancet. Neurology. 2016;15(3):279-291.
  6. Constantino JN, Zhang Y, Frazier T, Abbacchi AM, Law P. Sibling recurrence and the genetic epidemiology of autism. The American journal of psychiatry. 2010;167(11):1349-1356.
  7. Virkud YV, Todd RD, Abbacchi AM, Zhang Y, Constantino JN. Familial aggregation of quantitative autistic traits in multiplex versus simplex autism. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics. 2009;150B(3):328-334.
  8. Szatmari P, Liu XQ, Goldberg J, et al. Sex differences in repetitive stereotyped behaviors in autism: implications for genetic liability. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics. 2012;159B(1):5-12.
  9. Hartley SL, Sikora DM. Sex differences in autism spectrum disorder: an examination of developmental functioning, autistic symptoms, and coexisting behavior problems in toddlers. Journal of autism and developmental disorders. 2009;39(12):1715-1722.

 

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.

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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.

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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.

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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.

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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.

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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 women1,2, 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 ASD5,6. 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 autism7,8. 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 genes10,11. 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 synapses12,13. 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

  1. Wingate, M. et al. Prevalence of autism spectrum disorder among children aged 8 years – Autism and Developmental Disabilities Monitoring Network, 11 sites, United States, 2010. Morbidity and Mortality Weekly Report Surveillance Summaries 63, (2014).
  2. Fombonne, E. Epidemiology of pervasive developmental disorders. Pediatr. Res. 65, 591–598 (2009).
  3. Werling, D. M., Parikshak, N. N. & Geschwind, D. H. Gene expression in human brain implicates sexually dimorphic pathways in autism spectrum disorders. Nat. Commun. 7, 10717 (2016).
  4. BrainSpan: Atlas of the Developing Human Brain. (2013). at <http://www.brainspan.org&gt;
  5. Basu, S. N., Kollu, R. & Banerjee-Basu, S. AutDB: a gene reference resource for autism research. Nucleic Acids Res. 37, D832–6 (2009).
  6. Iossifov, I. et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature 515, 216–221 (2014).
  7. Voineagu, I. et al. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 474, 380–384 (2011).
  8. Gupta, S. et al. Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism. Nat. Commun. 5, 5748 (2014).
  9. Darnell, J. C. et al. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146, 247–261 (2011).
  10. Willsey, A. J. et al. Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism. Cell 155, 997–1007 (2013).
  11. Parikshak, N. N. et al. Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism. Cell 155, 1008–1021 (2013).
  12. Stevens, B. Neuron-astrocyte signaling in the development and plasticity of neural circuits. Neurosignals 16, 278–288 (2008).
  13. Schafer, D. P. et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74, 691–705 (2012).
  14. Schwarz, J. M., Sholar, P. W. & Bilbo, S. D. Sex differences in microglial colonization of the developing rat brain. J Neurochem 120, 948–963 (2012).
  15. McCarthy, M. M., Todd, B. J. & Amateau, S. K. Estradiol modulation of astrocytes and the establishment of sex differences in the brain. Ann. N. Y. Acad. Sci. 1007, 283–297 (2003).

 

Using the human brain to understand “omics” in autism

by Shannon Ellis, Ph.D. at Johns Hopkins University

Shannon

Shannon Ellis, PhD

Autism is a complex neurodevelopmental disorder with a definitively established genetic basis1. However, complete understanding of the genetic etiology remains elusive. While the role for certain CNVs in autism has been definitively established2,3 and exome sequencing studies have begun to uncover rare de novo mutations that play a role in the disorder4–9, we are far from identifying the names of the hundreds of genes likely contributing to the disorder.

While naming the genes that play a role in autism is critical, it has become increasingly clear that changes in the DNA sequence are only a first step toward complete understanding. Additionally, scientists acknowledge that they must know what the genes do, not only what they are. Therefore, our lab has begun to get a handle on what is altered at the level of gene expression and DNA methylation within the primary affected tissue in autism – the brain. This is part of a larger field called “omics”: meaning “genomics” (the study of DNA sequence), “transcriptomics” (the study of gene expression), “epigenomics” (the study of how genes are expressed, “proteomics” (how proteins are regulated by DNA expression) and “metabolomics” (the chemical processes of making and breaking down compounds). Our study focused on transcriptomics and epigenomics.

To understand the processes in the brains of people with autism, we had to study the brains of people with autism. Therefore, we worked with the Autism BrainNet (formerly the Autism Tissue Program) to obtain brain samples and extract RNA. We were interested in RNA because it is produced from DNA. Using DNA as a template, RNA is formed as the first step in creating proteins. The proteins are what carry out the function of the cell. The number of copies of RNA is a reflection of the gene expression of the cell: the more copies, the more gene expression. While differences in an individual’s DNA are undoubtedly of interest to the study of autism, it is also important to look for differences in gene expression and protein levels to fully understand the disorder. We used the RNA to look at the gene expression of about 14,000 genes. Additionally, in these same individuals, DNA samples were used to estimate methylation levels at cytosines across cytosine-rich regions of the genome.

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How DNA is transcribed to RNA then translated to proteins

Last year, we published some results on the transcriptomic part. When we looked at the gene expression, we identified three groups of genes that showed different patterns of expression between autism cases and controls. The first two groups included genes that influence the way neurons work, how they interact with each other, and how they grow and communicate to form the human brain. Interestingly, the genes that showed differences in gene expression were different genes than those identified in previous studies that, rather than looking at gene expression differences, looked to identify DNA differences important to autism. This demonstrates that genes that have differences in their DNA are different from those genes showing downstream differences at the level of gene expression. The third group was made up primarily of M2-microglia genes, suggesting in increased immune response in the brains of autistic individuals. We want to stipulate that this does not mean that alterations in the immune system of the brain cause autism. It could be that abnormal gene expression in the brain triggers an M2 microglia response. Future work is required before we can determine if the increased immune response leads to or is a result of autism. Nevertheless, from a treatment standpoint, this work provides pathways that, despite variable genetic causes, can be targeted for treatment in affected individuals going forward.

We moved this further to compare the gene expression overlap in the brains of people with autism with other neuropsychiatric disorders. Previous studies have shown that there is an overlap in which genes have DNA differences across neuropsychiatric disorders. To establish if this overlap holds up at the level of the transcriptome, we compared gene expression differences across three disorders: autism, schizophrenia, and bipolar disorder.  While there was little overlap between autism and bipolar disorder, there was significant overlap between the expression patterns in genes in autism and schizophrenia brains11, with consistent decreased expression at neuronal and synaptic plasticity genes across these two disorders. This work extended the known genetic overlap between neuropsychiatric disorders by establishing a relationship between alterations in gene expression found in both autism and schizophrenia.

Finally, as gene expression is directly regulated by DNA methylation, we looked to determine if DNA methylation differences play a role in autism.  Methylation is a process where a methyl group attaches to a part of a DNA sequence and turns down the expression of that gene. To look at DNA methylation, we looked at cytosines. Cytosines are places in our genome where these methyl groups normally attach. Thus far, most work has studied CpG methylation. This refers to when a methyl group attaches to a cytosine (C) that is directly next to a guanine (G) nucleotide. This CpG context is where methylation most frequently occurs in the genome. However, methylation can occur at cytosines next to other DNA nucleotides (C, T, or A), and this is referred to as CpH methylation. As CpH methylation occurs at higher levels in the brain relative to other tissues, we did not want to limit our study to CpG sites alone, but rather wanted to look for differences in CpH methylation as well. We found increased levels of methylation at CpH, but not CpG, sites globally within the autistic brain. We are currently working on why there is this difference and why it is seen in autism, but as CpH methylation is largely specific to the human brain (as compared to blood or other cells), it is a particularly compelling finding.

While we acknowledge we have not answered all the questions, we now have a better understanding of what is going on in the brain of individuals with autism. In particular, in addition to further establishing a relationship between schizophrenia and autism, this work not only highlights a role for increased immune activation within affected individuals, providing a particular pathway to target when considering future therapies, but also, for the first time, suggests a role for increased methylation at cytosines within the CpH context in the brains of autistic individuals.

 

References:

  1. Gaugler, T. et al. Most genetic risk for autism resides with common variation. Nat. Genet. 46, 881–885 (2014).
  2. Marshall, C. R. & Scherer, S. W. Detection and characterization of copy number variation in autism spectrum disorder. Methods Mol. Biol. Clifton NJ 838, 115–135 (2012).
  3. Sebat, J. et al. Strong Association of De Novo Copy Number Mutations with Autism. Science 316, 445–449 (2007).
  4. Sanders, S. J. et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature (2012).
  5. Yu, T. W. et al. Using Whole-Exome Sequencing to Identify Inherited Causes of Autism. Neuron 77, 259–273 (2013).
  6. Iossifov, I. et al. De Novo Gene Disruptions in Children on the Autistic Spectrum. Neuron 74, 285–299 (2012).
  7. O’Roak, B. J. et al. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat. Genet. 43, 585–589 (2011).
  8. Neale, B. M. et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature (2012).
  9. De Rubeis, S. et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515, 209–215 (2014).
  10. Gupta, S. et al. Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism. Nat. Commun. 5, 5748 (2014).
  11. Ellis, S. E., Panitch, R., West, A. & Arking, D. E. Transcriptome Analysis of Cortical Tissue Reveals Shared Sets of Down-Regulated Genes in Autism and Schizophrenia. bioRxiv 29132 (2016).

 

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Boaz Barak, ASF fellow, from MIT

This blog was written by Dr. Boaz Barak, an ASF fellow and an author on a recent publication  in Neuron that used animal models to show that different mutations of the same gene can lead to different psychiatric disorders.  The study was led by Dr. Yang Zhou in Prof. Guoping Feng’s lab at MIT.   In this case, one mutation has been associated with schizophrenia and the other with autism. Dr. Barak explains their findings below.

Autism is one of the most heritable neuropsychiatric disorders. Mutations in genes associated with autism will eventually lead to the expression of malfunctioning proteins. One such gene that is known to be mutated in Phelan-McDermid syndrome is Shank3, encoding the postsynaptic protein SHANK3.  People with Phelan-McDermid Syndrome, or PMS, often show symptoms of autism.

To study the role of genetic mutations in autism etiology, our lab engineered mouse models that express the mutated gene in their brains, allowing the researchers to study the behavioral, physiological and biochemical consequences of these gene mutations.

We induced two different mutations but in the same gene, Shank3, based on human mutations found in patients. By doing so, we showed evidences how different mutations in the same gene can lead to two different disorders, autism and schizophrenia.

Interestingly, we found that mice with the autism-related mutation (InsG3680), demonstrate impairments earlier in life than those with the schizophrenia-related  mutation (R1117X), coinciding with the early onset of autism spectrum disorders symptoms. Specifically, starting from very early age, impaired electrical activity of neurons was measured in the striatum, a brain region important for integration and coordination of multiple neurological processes necessary for normal behavior. Along with the abnormal neuronal activity of cells, we found impaired social behavior in the mice with the mutation, together with extensive repetitive behavior. Looking for biological findings that might explain these abnormalities, we found molecular changes in the composition of proteins in the synapse and the transcripts (mRNA) responsible for the expression of those synaptic proteins.

Overall this study shed new light on the pathophysiology of autism and schizophrenia, and enables the research community to study the consequences of two different human-based mutations in novel mouse models.

Why is this important for people with autism?  Hopefully, the data published will help in developing drugs targeted to fix the physiological and the behavioral abnormalities of the Shank3 mutation. Improved understanding of such syndromic cases will lead to better basic understanding of also other types of neurodevelopmental disorders, and ultimately, the discussed mouse models will assist the research community in validating potential drugs before testing them on people with autism.

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