Mini Brains Model Autism

Patient-derived organoids reveal autism spectrum disorder–associated anomalies.

By | July 16, 2015

Human brain organoidJESSICA MARIANIAn examination of tiny, brain-like organoids generated from the skin cells of patients with autism spectrum disorder (ASD) suggests that the condition may be associated with an overproduction of inhibitory neurons, among other things. The study, published today (July 16) in Cell, reveals that although the patients’ symptoms arose spontaneously, their brain cells behaved similarly in vitro.

“These are patients with idiopathic autism that do not share any genetic causes, and yet the authors find phenotypes shared between their cells. That’s impressive,” said neuroscientist and stem cell biologist Alysson Muotri of the University of California, San Diego, who was not involved in the study. “If someone had asked me, I would have said, ‘You won’t find anything in common, it’s probably going to be a mixed bag.’ But no . . . there seems to be key things that are dysregulated in all of them.” (See “Opinion: New Models for ASD,” The Scientist, May 14, 2015.)

Indeed, “one of the most exciting aspects of the work is that it manages to tackle idiopathic neurological disease,” agreed Magdalena Götz of Ludwig-Maximilians-University Munich, who also did not participate in the research.

ASD is a collection of complex neurodevelopmental disorders that are characterized by social deficits, communication difficulties, repetitive behaviors and, in some instances, cognitive problems. Studies into familial cases of ASD have identified certain genes that confer risk for the disorders, but the majority of cases are idiopathic, meaning their origins are a mystery.

Flora Vaccarino at Yale School of Medicine recognized that induced pluripotent stem cell (iPSC) technology—in which adult cells are reverted to embryonic-like cells and then directed to specific fates—would provide a “unique opportunity” to investigate idiopathic ASD’s obscure roots, she said. “I immediately realized that this could be used to reenact stages of neurodevelopment that were almost impossible to study in humans.”

To this end, her team obtained skin cells from four adolescent male ASD patients and their four biological fathers who do not have ASD. The team then converted these skin cells into iPSCs and subsequently directed them to develop into small cellular aggregates that resembled features of the telencephalon—the embryonic structure from which the brain’s cerebrum develops.

Although these patient- and control-derived organoids shared similar overall structures and electrical activities, there were considerable and reproducible differences in gene expression between ASD mini brains and their non-ASD counterparts during organoid development, explained Vaccarino. ASD patient organoids tended to have upregulated expression of genes involved in cell proliferation, neuronal development, and synapse assembly, she said.

To confirm these results Vaccarino’s team measured the proliferation rates of the organoid cells and found that, at early stages of development, “the cells of the patients divide faster than the fathers’,” said Vaccarino. The team then asked whether some or all neurons increased in number. “That’s when we discovered that the glutamatergic [excitatory] neurons were not affected, but the GABAergic [inhibitory] neurons were increased,” she added.

The team re-examined the gene-expression data to see if there were clues as to why inhibitory neurons were getting a boost. The researchers discovered that among the consistently upregulated transcripts in the patient organoids was the messenger RNA encoding FoxG1a transcription factor important for telencephalon development. Suppressing the expression of the FoxG1 transcript in patient-derived organoids restored normal inhibitory neuronal numbers.

Exactly how an increase in FoxG1 and inhibitory neurons might lead to ASD is unclear, said Vaccarino, but it’s possible that excess inhibition early in development “is affecting the way neurons connect with each other.”

Beyond pointing to possible mechanisms associated with the development of ASD, the results indicate that patient-derived organoids may be helpful for studying other idiopathic neurological disorders, such as Alzheimer’s disease, amyotrophic lateral sclerosis, or Parkinson’s. “We think that these are very complex disorders and that it is probably very hard to find similar molecular pathways in idiopathic groups,” said Muotri, “but maybe not. . . . This paper offers the perspective that it’s doable.”

J. Mariani et al., “FOXG1-dependent dysregulation of GABA/glutamate neuron differentiation in autism spectrum disorders,” Cell, 162:1-16, 2015.

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July 17, 2015

I am unfamiliar with the authors techniques; is age a factor in the cellular expression/ behavior of the re-reverted cells? I would find it interesting to compare the test subjects to their non autistic siblings rather than their male parents. Have other stuudies been done on this model of gene expression/ development with age of the sample subject as the primary factor? In any case I thank the authors for their ground breaking contributuion to the field. GTL

Avatar of: PastToTheFuture


Posts: 76

July 17, 2015

Nature, Nurture, Function, Fracture, Autism, Ad Nausium.

Somehting odd, from my point of view saying that autism has a genetic foundation supports my work. Before this, my best evaluation said that about 33% of autism is genetic bsed. If I understand this, it says it is far higher. If it goes over 66% though, there are some questions that really need asking.  If that is so, even 66%, it pretty near has to be "de novo mutations" or "non integral genes" as I have called them for over 40 years, because they are broken, not fresh. I wonder when anyone is going to notice that CRISPR is not going to be able to fix a problem like that? Welllll.... I did publish the solution in "Transition To A New Human Ecology" if anyone wants to glance at it.

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Posts: 23

July 17, 2015

Fascinating, I would love to see more of the reproducibility with siblings as well. The more elusive ASD daughters and their mothers would be equally fascinating. Nothing like a well designed experiment to get the mind flowing.
Avatar of: lynz60


Posts: 1

July 20, 2015

Awesome article using iPSCs for a purpose that never would have occured to me. A couple of queries though. Firstly what technique was used to revert the somatic cells? Secondly, I query why both parents somatic cells were not reverted and tested. After all the maternal and paternal genes contribute to the childs. Would it not be a more robust study if it examined the behaviour of both parents reverted cells to see if the anomalies were or were not apparent in both iPSC lines?

Avatar of: Hugh-F-61


Posts: 67

July 25, 2015

Excess inhibition actually fits well with Asperger's spectrum behaviour. I have taught several undergraduates with this designation, and I suspect that many Nobel prize winners are slightly autistic. The common feature is a tendency to obsession and extreme concentration and specialisation of thought. We are "concious" of whatever thought processes rise to the top of the pile, and to do this these neuronal circuits must repress other neuronal circuits. For a brain to concentrate it has to inhibit distractions. "Autistic" students are not affected by social cues and will readily interupt conversations with their views; I suggest that it is not that they don't recognise the cues but that they inhibit any response to these cues, because in some  cases where it fits their objectives I have found them to be extremely manipulative and excellent liers, showing that they fully understand what motivates other people. Once they sieze on an idea or activity they are difficult to change or distract. If the activity is work they are very productive, if it is trivial they have OCD, if it is an internal loop they have severe autism or schizophrenia. The same genetic loci are associated with all these conditions. Whatever they do at the tiime they do it almost to the exclusion of everything else. All other brain activity is inhibited. This reduces the value comparisons that we consider normal, and may prevent unrealistic thoughts being recognised by comparison with objective reality.

Avatar of: Pretzelcoatl


Posts: 1

Replied to a comment from Hugh-F-61 made on July 25, 2015

August 4, 2015

I don't know your scientific background, but I would be wary of simply equating excess inhibitory neurons at a micro level with greater inhibition at the macro (behavioral or cognitive) level. Because of the way neurons are strung together, the role of inhibitory neurons in neural circuits can be complex; for example, in some cases a "behavior" (broadly speaking) can be released by inhibiting inhibitory neurons - a kind of neural case of two negatives equaling a positive.

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