Summary: Researchers used human brain organoids—often called “mini‑brains”—to investigate the early origins of autism spectrum disorder (ASD). Their work indicates a disruption in the balance of excitatory cortical neurons in the forebrain of individuals with ASD, offering new insight into how developmental changes in utero may contribute to the condition.
This advanced organoid technology recapitulates aspects of prenatal brain development and helps identify when and how ASD-related differences emerge. The findings build on many years of genetic and cellular research into autism and point to specific molecular mechanisms that affect early neuronal differentiation.
Key facts:
- Scientists modeled early brain development using human forebrain organoids and detected an altered balance of excitatory cortical neuron subtypes in organoids derived from people with ASD.
- These organoids began as skin cells taken from participants, reprogrammed into induced pluripotent stem cells, and then directed to develop into three‑dimensional brain tissue that mimics early cortical neurogenesis.
- The neuronal imbalance is linked to changes in the activity of transcription factors—genes that regulate cell fate decisions during the earliest stages of cortical formation.
Source: Mayo Clinic
Overview: Scientists from the Mayo Clinic and Yale University applied human forebrain organoids to model idiopathic autism and discovered that alterations in excitatory cortical neurons may underlie core features of ASD. The study is published in Nature Neuroscience.
Findings
The research team observed an atypical distribution of excitatory neuron subtypes in the forebrain organoids derived from individuals with autism. The nature and direction of this imbalance varied with characteristics such as head size, suggesting there may be distinct developmental trajectories associated with different ASD presentations.
“Organoid technology allowed us to recreate the developmental changes that occurred in these patients while they were in the womb—a critical window when autism spectrum disorder is thought to arise,” said Alexej Abyzov, Ph.D., a genomic researcher at the Mayo Clinic Center for Individualized Medicine and a senior author of the study.
What is autism spectrum disorder
Autism spectrum disorder is a neurodevelopmental condition that alters how individuals perceive, process, and respond to social and sensory information. Symptoms and functional impact span a broad range, which is why the condition is described as a spectrum. The diagnostic category includes what were previously separated diagnoses such as Asperger’s syndrome and other pervasive developmental disorders.
In the United States, estimates from the Centers for Disease Control’s Autism and Developmental Disabilities Monitoring Network indicate that nearly 1 in 36 children has been identified with ASD. Prevalence estimates underline the importance of understanding the biological roots and early developmental mechanisms of autism.
More about “mini‑brains”
For this study, researchers created forebrain organoids—small, three‑dimensional clusters of cells that model aspects of human cortical development. The organoids originated from skin cells donated by study participants with ASD. Those skin cells were reprogrammed into induced pluripotent stem cells (iPSCs), which can be guided to form many types of cells, including neurons and supporting brain cell types.
To analyze how cell types and gene activity differed during development, the team used single‑cell RNA sequencing. This technique measures gene expression in individual cells, allowing researchers to map cell identities and developmental pathways at high resolution. In total, the study profiled 664,272 brain cells across three stages of early development, revealing altered proportions of excitatory neuron subtypes in ASD organoids.
The researchers traced the neuronal imbalance to divergent activity of specific transcription factors—molecules that instruct precursor cells which neuronal fate to adopt during early cortical development. Those changes in transcriptional regulation help explain how small molecular differences can cascade into broader alterations in neural circuitry.
Building evidence
This work extends more than a decade of research on autism by Dr. Abyzov and collaborators, including Flora Vaccarino, M.D., of Yale University. Previous studies using organoids identified molecular and cellular differences between organoids from people with autism and those without, and highlighted the deregulation of transcription factors such as FOXG1 as a potential contributor to developmental divergence.
“Autism is largely influenced by genetics. Our long‑term goal is to better estimate autism risk prenatally and, eventually, to identify opportunities for intervention before birth. Achieving that will require a detailed understanding of how brain developmental programs become disrupted—research areas where organoids can be particularly informative,” said Dr. Abyzov.
For a complete list of authors, disclosures, and funding, consult the published study in Nature Neuroscience.
About this autism research news
Author: Emily DeBoom
Source: Mayo Clinic
Contact: Emily DeBoom – Mayo Clinic
Image credit: Neuroscience News
Original research (open access): “Modeling idiopathic autism in forebrain organoids reveals an imbalance of excitatory cortical neuron subtypes during early neurogenesis” by Alexandre Jourdon et al., Nature Neuroscience.
Abstract (summary):
Idiopathic autism spectrum disorder is highly heterogeneous, and it remains unclear which convergent biological processes give rise to clinical features. Using cortical organoids and single‑cell transcriptomics, the study modeled forebrain development differences between boys with idiopathic ASD and their unaffected fathers across 13 families. The transcriptomic data indicate that ASD pathogenesis in individuals with enlarged heads (macrocephalic) and those with typical head size (normocephalic) involves opposite disruptions in the balance between excitatory dorsal cortical plate neurons and other early neuronal lineages, such as neurons from the putative preplate. These imbalances arise from divergent expression of transcription factors that drive early cortical cell fate decisions. Although the researchers did not identify genomic variants in the probands that fully explain the transcriptomic alterations, there is significant overlap between altered transcripts and ASD risk genes affected by rare variants, suggesting some convergence between rare genetic forms of ASD and the developmental transcriptome in idiopathic cases.