A University of California San Diego study finds that differences in brain development associated with autism begin in utero, with larger and faster-growing brain cortical organoids in autistic toddlers correlating with more serious symptoms. This research opens new avenues for understanding and potentially treating autism.
Researchers at the University of California San Diego have found that an unusually large brain could be the first sign of autism, potentially detectable as early as the first trimester.
Some children with autism face serious and persistent challenges, including developmental delays, social difficulties, and possibly an inability to speak. Meanwhile, others may experience milder symptoms that subside over time.
The disparity in results remained a mystery to scientists until now. A new study, published in Molecular autism by researchers at the University of California at San Diego, is the first to shed light on the subject. Among his findings: The biological basis of these two subtypes of autism develops in utero.
Researchers used blood stem cells from 10 toddlers, ages 1 to 4, with idiopathic autism (in which no monogenic cause has been identified) to create brain cortical organoids (BCOs) or models of the fetal cortex. They also created BCOs from six neurotypical toddlers.
Results on brain development
Often called gray matter, the cortex lines the exterior of the brain. It contains tens of billions of nerve cells and is responsible for essential functions such as consciousness, thinking, reasoning, learning, memory, emotions and sensory functions.
Among their findings: BCOs of autistic toddlers were significantly higher – about 40% – than those of neurotypical controls, according to two sets of studies carried out in different years (2021 and 2022). Each cycle involved the creation of hundreds of organoids from each patient.
Researchers also found that abnormal BCO growth in autistic toddlers correlated with the presentation of their illness. The larger the size of a toddler’s BCO, the more severe their social and language symptoms were later in life and the larger their brain structure on MRI. Toddlers with excessively enlarged BCOs had higher than normal volume in social, language, and sensory brain areas compared to their neurotypical peers.
“The bigger the brain, the better is not necessarily true,” said Alysson Muotri, Ph.D., director of the Orbital Integrated Space Stem Cell Research Center at the Sanford Stem Cell Institute (SSCI) at the university. The SSCI is led by Catriona Jamieson, MD, PhD, a leading physician-scientist in cancer stem cell biology whose research explores the fundamental question of how space modifies cancer progression.
“We found that in the brain organoids of toddlers with profound autism, there are more cells and sometimes more neurons – and that’s not always for the better,” added Muotri, who is also professor in the departments of pediatrics and cellular and molecular medicine. at the UC San Diego School of Medicine.
Additionally, the BCOs of all autistic children, regardless of severity, increased about three times faster than those of neurotypical children. Some of the largest brain organoids – from children with the most severe and persistent cases of autism – also saw accelerated neuron formation. The more severe a child’s autism, the faster their BCO grows – sometimes to the point of developing excess neurons.
Unique aspects of the study
Eric Courchesne, Ph.D., a professor in the School of Medicine’s Department of Neuroscience who co-led the research with Muotri, called the study “one of a kind.” Matching data on autistic children — including their IQ, symptom severity and imaging like MRI — with their corresponding BCOs or similar stem cell-derived models makes enormous sense, he said. But curiously, such research had not been undertaken before their work.
“The main symptoms of autism are social, emotional and communication problems,” said Courchesne, who is also co-director of the Autism Center of Excellence at UC San Diego. “We need to understand the underlying neurobiological causes of these challenges and when they begin. We are the first to design an autism stem cell study on this specific and central question.
Autism, a complex set of progressive disorders, has long been assumed to begin before birth and involve multiple stages and processes. Although no two autistic people are alike – just as no two neurotypical people are alike – those who suffer from a neurodevelopmental disorder can generally be grouped into two categories: those who have severe difficulties social and require lifelong care, and may even be non-verbal, and those who have a milder version of the illness and eventually develop good language skills and social relationships.
Scientists have not been able to determine why there are at least two groups of autistic individuals. They also weren’t able to identify autistic children before birth, much less predict the severity of their condition.
Now that Courchesne and Muotri have established that brain proliferation begins in the womb, they hope to identify the cause, with the goal of developing a therapy that could facilitate intellectual and social functioning in those affected.
Reference: “Embryonic origin of two ASD subtypes of social symptom severity: the larger the size of the cerebral cortical organoid, the more severe the social symptoms” by Eric Courchesne, Vani Taluja, Sanaz Nazari, Caitlin M. Aamodt, Karen Pierce, Kuaikuai Duan, Sunny Stophaeros, Linda Lopez, Cynthia Carter Barnes, Jaden Troxel, Kathleen Campbell, Tianyun Wang, Kendra Hoekzema, Evan E. Eichler, Joao V. Nani, Wirla Pontes, Sandra Sanchez Sanchez, Michael V. Lombardo, Janaina S. de Souza, Mirian AF Hayashi and Alysson R. Muotri, May 25, 2024, Molecular autism.
DOI: 10.1186/s13229-024-00602-8
Study co-authors include Vani Taluja, Sanaz Nazari, Caitlin M. Aamodt, Karen Pierce, Kuaikuai Duan, Sunny Stophaeros, Linda Lopez, Cynthia Carter Barnes, Jaden Troxel, Kathleen Campbell, Tianyun Wang, Kendra Hoekzema, Evan E .Eichler. , Joao V. Nani, Wirla Pontes, Sandra Sanchez Sanchez, Michael V. Lombardo and Janaina S. de Souza.
This work was supported by grants from the National Institute on Deafness and Communication Disorders, the
” data-gt-translate-attributes=”({“attribute”:”data-cmtooltip”, “format”:”html”})” tabindex=”0″ role=”link”>National Institutes of Health, the California Institute for Regenerative Medicine and the Hartwell Foundation. We thank the parents of San Diego toddlers whose stem cells were reprogrammed into BCO.