What Causes Autism? New Research Uncovers a Key Factor in Brain Development

Brain Signals Rotating Test

The findings of this research reveal a significant component in the underlying causes of neural tube birth defects, intellectual disabilities, and autism risk.

Researchers from Texas A&M College of Medicine have provided answers to important questions concerning how the neocortex develops, providing new information about the root causes of intellectual disabilities.

A significant advancement in our understanding of how the brain develops has been accomplished by researchers at Texas A&M University College of Medicine. This new research advances our understanding of how the region of the brain that distinguishes humans from other animals develops and sheds light on what causes intellectual disabilities, such as autism spectrum disorders.

 For many years, scientists have recognized a significant relationship between mammalian intelligence and a thin layer of cells in the neocortex, the region of the brain that governs higher-order processes like cognition, perception, and language. The neocortex’s surface area reflects how highly developed an organism’s mental ability is. For instance, the human neocortex is only around three times thicker than the mouse equivalent. However, the human neocortex has a 1,000-fold larger surface area than that of mice. Autism spectrum disorders and intellectual impairments are among the developmental deficiencies caused by malformations in this region of the brain.

What is unknown is how evolutionary expansion of this section of the brain happens selectively in favor of growing the neocortex’s surface area at the cost of increasing its thickness. An important aspect of this process is how the initial populations of neural stem cells, which serve as the brain’s building blocks, distribute themselves.

“There are many, what we’ll call, individual processing units that are horizontally arranged in the neocortex. The more surface area you have, the more of these processing units you can accommodate,” said Vytas A. Bankaitis, Distinguished Professor at the College of Medicine, E.L. Wehner-Welch Foundation Chair in Chemistry, and co-author of this study, which was published in Cell Reports. “The question is, why is the neocortical surface area so much greater relative to its thickness as one climbs up the mammalian evolutionary tree? Why do neural stem cells spread themselves in a lateral direction as they proliferate and not pile on top of each other?”

This question is key because when the cells do not spread out, but instead pile up, it creates a thicker neocortex with a smaller surface area — a characteristic that has been observed in cases of intellectual disability and even autism.

“One of the most studied genetic causes of intellectual disability is a mutation in a gene that was originally called LIS1,” said Zhigang Xie, assistant professor at the College of Medicine and co-author of the study. “This genetic mutation will cause a smooth brain, which is associated with intellectual disability. And one typical observation is that the neocortex of the patient is thicker than normal. There are also very recent studies that identify common differences in the brain of autism that include abnormally thickened regions of the neocortex in those individuals.”

Scientists have known for some time that as neural stem cells divide, their nuclei move up and down within their anatomical space as a function of the cell cycle, a process called interkinetic nuclear migration. They do so by employing a cytoskeletal network that acts like train tracks with engines that move the nuclei up or down in a closely regulated manner. Although several ideas have been proposed, it remains an enigma why the nuclei move in this way, how this network of train tracks is controlled, and what role interkinetic nuclear migration plays in development of the neocortex.

In their study, Xie and Bankaitis provide answers to these questions.

As for why, Bankaitis explains that when there are so many cells so close together in the embryonic stage of neocortical development, the movement of their nuclei up and down causes opposing upward and downward forces that spreads the dividing neural stem cells out.

“Think about a tube of toothpaste,” Bankaitis said. “If you were to take that toothpaste tube, put it between your hands, push up from the bottom and push down from the top, what would happen? It would flatten and spread out. That’s essentially how this works. You have an upward force and a downward force caused by the movement of the nuclei that spreads these cells out.”

Xie and Bankaitis also demonstrate how the cells do this by linking together several distinct pathways that cooperate to “tell” the newborn neural stem cells where to go.

“I think for the first time, this really puts together molecules and signaling pathways that indicate how this process is controlled and why it would be linked or associated with neurodevelopmental deficiencies,” Bankaitis said. “We have taken a biochemical pathway, linked it to a cell biological pathway, and linked it to a signaling pathway that talks to the nucleus to promote the nuclear behavior that generates a force that develops a complicated brain. It’s now a complete circuit.”

The results of this study uncover an important factor in the underlying causes of autism risk, intellectual disabilities and neural tube birth defects. The new knowledge on the basic principles regulating the shape of the neocortex will also help the design of in vitro brain culture systems that more accurately reflect the developmental processes of interest and improve the prospects for neurological drug development.

“While there might prove to be many reasons why a neocortex thickens instead of spreads, our work provides a new perspective on why patients with autism and intellectual disabilities often display a thicker cortex,” Xie said. “The fact that the LIS1 gene product is a core regulator of nuclear migration, including the interkinetic nuclear migration that we study in this work, supports the conclusions we reach in this paper.”

Reference: “Phosphatidylinositol transfer protein/planar cell polarity axis regulates neocortical morphogenesis by supporting interkinetic nuclear migration” by Zhigang Xie and Vytas A. Bankaitis, 31 May 2022, Cell Reports.
DOI: 10.1016/j.celrep.2022.110869

The study was funded by the NIH/National Institutes of Health and the Robert A Welch Foundation.

17 Comments on "What Causes Autism? New Research Uncovers a Key Factor in Brain Development"

  1. Damon Matthew Wise Âû | August 3, 2022 at 11:16 am | Reply

    I just wonder how does the thicker neucortex in Humans and other mammals collate to the Âûtistic and Co-morbidity genes that we Neurodiverse persons have and explain brighter hundreds of percent more almost hyperactivity in Right hemisphere, Tempora, Frontal lobes and Amygdala, compared to greyzones and work around in reduced activity left hemisphere and the thousands of Autism Genome Project Autistic, Co-morbidity and mutations in a few million Autistic and Co-morbidity confirmed participants recorded as 1 in 5.8 and 1 in 5.9 in Denmark and Sweden by cottaging of many multiple traits, Co-morbidities and coping mechanisms.

  2. Autism isn’t a disability. If autism is a disability, thing so is womanhood.

  3. Ok, Peter. Once you figure out what causes the disability in those identified autistic then you can make that declaration. Until then, and within the household I exist in, there are strengths in the identity, but in the same vein, there are also several disabling aspects as well. Hence it IS a disability. When people make bold statements like this, they are slowly creating a reality where supports could be taken away to those most profoundly affected since they are trying to sell the idea that “it’s not a disability.”

  4. Tylenol is currently being called out for knowing that their drug causes autism and not releasing those findings.

  5. While plenty of autistic people are disabled I’m not sure we can really say autism is a disability. It’s certainly not an intellectual disability. There is a high co-morbidity with other disorders, some of which are more of a disability than others but there are plenty of autistic people who are no less capable than any autistic person. Sometimes the same traits that appear to be a disability in some situations can be an advantage in others. My son is very sensitive to sound, he gets overwhelmed easily and I can see how and why that’s perceived as a disability. However, I have the same sensitivity and, while it was stressful and difficult in childhood, as an adult I have a great ear for subtle differences in sound. That’s an advantage in music and vocal impressions, it also allows me to identify what my children are doing without looking at them. I know the sound of pretty much every toy and surface. So perhaps suitability to environment varies and it’s not so clear cut as disability/not a disability.
    This can apply to traits that no one calls disabilities too. Some people love cold weather, I can’t function in cold weather at all but I’m not uncomfortable at 90 degrees. My lack of tolerance to the cold isn’t a disability but it does make me unsuited to a cold environment. In the same way we could say that autistic children who have meltdowns in chaotic environments are simply unsuited to noisier, more urban environments.
    Without a significant improvement of our understanding of what exactly autism is, how it works, where to draw the line between autism and its comorbidities, I suppose it’s open to debate.
    As a side note, when someone says “autism isn’t a disability”, it might be worth considering that they could be autistic and not see themselves as disabled, or the parent of an autistic child who doesn’t find the experience disabling.
    I am autistic and don’t consider myself disabled. I have two children who have been diagnosed with autism, one of whom is non-verbal. Those diagnoses don’t guarantee disability payments in and of themselves in my corner of the world anyway.

    • “plenty of autistic people who are no less capable than any allistic person.” Autocorrect doesn’t know the word allistic aparently.

  6. How can we trust any research coming out of Texas a&m when they allow such egregious conflicts of interest in their programs?

    Doing beef research and taking donations from organizations connected to the beef industry, and then not reporting it in their research?

    They better get their house in order or might as well shut down the school.

  7. Reading this make more questions, why does it affect more boys? and why is it that we are seeing so many cases? This finding is great but we need to find out the cause enviro, consumption foods products? We have 2-3% of Canadians are affected by this diagnosis.

  8. My IQ is 135. I have hyperlexia with full reading comprehension. I have read a lot of credible medical literature which states that Autism/ASD is a neurodevelopmental disorder, not an intellectual disorder.

  9. Autism isn’t an intellectual disability.
    The first paragraph says “… and sheds light on what causes intellectual disabilities, such as autism spectrum disorders”. The rest of the article uses “intellectual disabilities and autism” which accurately reflects the research findings.
    This needs to be edited as makes the authors appear ignorant to anyone who knows anything about autism.

  10. Try tô find reasons of autism in vaccination.

  11. As someone who can or at least say I am not autistic not that I have been told by a Dr so please read this as a possibly dumb by honest question anyway but my best friend has a son that is autistic or has a form of it possibly we are close and watched him as he grew up and I noticed some of the things about him seems like habits ,disliking change and not understanding sarcasm so I guess my question is was he born autistic because his sister and his brother are not was it in his genes or d.n.a.? Or can children develop autism threw outside factors?

  12. While there may indeed be some truth to this, as I think there is, there is still much about it I am questioning. Yes, this research supposedly provides some possible answers, but there are also quite a few unanswered questions and vital missing pieces of this complicated “intellectual disability” puzzle. Which for the record, is incorrectly titled since Autism is in fact NOT technically considered an intellectual disability, but instead a neurological one. And not even a disability. It’s labeled a disorder. And many people would argue with that. But for time, sanity, and technicality sake, it’s a disorder. Regardless, I wish I had more hope in this but if the people doing this work are comparing and calling Autism the same as intellectual disabilities…well, let’s just say i have my doubts.

  13. This was a great article. Hats off to the team finding these correlations and observations. These are the findings that lead us in directions that hold answers.

    It’s so sad to read these comments. Questioning these scientific finding because of the funding channels uses as an o stitution..situation… arbitrarily saying that autism shouldn’t be considered a disability because of personal observations of qualitative factors is mind blowing. It’s as though there is an entire wave of people who are not being taught how anything on the world actually works. Or why. Clearly discernment has left the building.

    If one wants to protect the status quo of autism, I just can’t begin to fathom why but thats not important, which is something alot of you could learn, but back to the issue, if you convince the world over that autism should not be looked at as a disabilty then you better take a long hard look at yourself in the mirror and ask yourself a few questions:
    1. Do you have any business voicing opinions like that on platforms that are far reaching? Let me translate for the younger crowd… do you have any scientific/educational/vocational credentials that support your words as anything more than an opinion or thought? If so, pipe down.
    2. If your message hits and the world over decides it is not a disabilityany more, research will cease. Do I understand the power of change? Have I performed efficacy studies that support making this change or am I only doing this for the fluffy feelings Inside me?

    Honestly, I read about all these school shootings and I’m always surprised when I find out the shooter WASNT a teacher.

    Good luck to those of you who are unknowingly barking for research, similar to that performed in this article, to stop. You’re the real disability in the world. You’ve convinced us all.

  14. My son was born in 2009. Extra genetic material on line 16, tourette’s syndrome followed at age 3, ADHD, OCD, and lastly behavioral problems. No doctor out of the 20+ doctors we seen knew how to treat or help him. I am sad daily as I had to place him in his father’s care. I have 6 children under 12yo. He would look for any opportunity to get too one of his sister’s and beat them until he seen blood. He would laugh and think it was so cool. I wish I knew what went so wrong.

  15. I am a 73 year old recently retired physician, very successful in my 45 year career. As my brain has gradually reaclimated to “normal” life after 45 years on constant “high alert”, I have noticed a reemergence of intellectual, cognitive and social patterns of function which are very suggestive of ASD, and which were evidently unlearned during my decades of acquired “normal” behavior. Throughout my life I have dealt with often awkward and cringy social abilities. Many professional, personal and romantic relationships suffered from my unique ability to sabotage them. Since I come from a family in which nearly all males of one lineage (my paternal grandfather’s) are clearly on the spectrum, I’ve realized, for the first time that I am as well. A few of these males are/were severely disabled, but much more frequently they are like me — reasonably social but with an awkwardness which is counterbalanced by savant abilities which allow us to reach high levels of mastery in fields like medicine and teaching. All of us seem to have high levels of social justice awareness, which only seems to add to our perceived level of occupational success.
    It is becoming clear to me, looking back on my family’s four generations of approximately 90% incidence of ASD among the men, that this persistence of a high incidence of ASD would not occur unless the autistic spectrum disorders are a normal variant of human intellectual and social development. In other words, ASD must be normal-ish, must have served some sort of social purpose during the Ice Age, for them to persist this long. It’s not hard to imagine there being an advantage for a tribe to include a member who thinks somewhat like game animals, a la Temple Grandin; or a member like myself who appears to have an ability to see connections between seemingly unrelated abstractions; or a member who sees off-kilter dream-like narrative explanations for disturbing events in the environment — proto- myths and stories. It may be that our abilities are not needed since the evolution of culture, or perhaps these functions have been assumed and performed by new agents within the culture.
    Whatever, it’s clear to me, at least, that the ASD are not disorders, developmental abberrations or illnesses. Our oddball abilities should be cultivated, while we are taught how to work around our cringiness.

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