Summary: Atypical brain development begins at the very earliest stages of brain organization, at the level of individual neurons.
Autism is a neurodevelopmental condition that researchers are now tracing back to prenatal development, even though the disorder is not diagnosed until at least 18 months of age. A new study now shows in human brain cells that the atypical development starts at the very earliest stages of brain organization, at the level of individual brain cells.
The study from scientists at King’s College London and Cambridge University, UK appears in Biological Psychiatry.
Deepak Srivastava, PhD, from the MRC Centre for Neurodevelopmental Disorders and Department of Basic and Clinical Neuroscience at King’s College London, who supervised the study, said: “In this study we used induced pluripotent stem cells, or iPSCs, to model early brain development. Our findings indicate that brain cells from autistic people develop differently to those from typical individuals.”
The researchers isolated hair samples from nine autistic people and six typical people. By treating the cells with an array of growth factors, the scientists were able to drive the hair cells to become nerve cells, or neurons–much like those found in either the cortex or the midbrain region. iPSCs retain the genetic identity of the person from which they came and the cells re-start their development as it would have happened in the womb, providing a window into that person’s brain development.
Dwaipayan Adhya, PhD, a molecular biologist at the Autism Research Centre in Cambridge and Department of Basic and Clinical Neuroscience at King’s College London, said: “Using iPSCs from hair samples is the most ethical way to study early brain development in autistic people. It bypasses the need for animal research, it is non-invasive and it simply requires a single hair or skin sample from a person.”
At various stages, the authors examined the developing cells’ appearance and sequenced their RNA, to see which genes the cells were expressing.
At day 9, developing neurons from typical people formed “neural rosettes,” an intricate, dandelion-like shape indicative of typically developing neurons. Cells from autistic people formed smaller rosettes or did not form rosettes at all. And key developmental genes were expressed at lower levels in cells from autistic people.
At days 21 and 35, the cells from typical and autistic people differed significantly in a number of ways, suggesting that the makeup of neurons in the cortex differs in the autistic and typically developing brain.
John Krystal, PhD, Editor-in-Chief of Biological Psychiatry, said of the findings: “The emergence of differences associated with autism in these nerve cells shows that these differences arise very early in life.”
In contrast to the differences seen in cortical neurons, cells directed to develop as midbrain neurons – a brain region not implicated in autism dysfunction – showed only negligible differences between typical and autistic people.
“The use of iPSCs allows us to examine more precisely the differences in cell fates and gene pathways that occur in neural cells from autistic and typical individuals. These findings will hopefully contribute to our understanding of why there is such diversity in brain development,” said Dr. Srivastava.
Simon Baron-Cohen, PhD, Director of the Autism Research Centre at Cambridge, who co-led the study, added, “Some people may be worried that basic research into differences in the autistic and typical brain prenatally may be intended to ‘prevent,’ ‘eradicate,’ or ‘cure’ autism. This is not our motivation, and we are outspoken in our values in standing up against eugenics and in valuing neurodiversity. Such studies will lead to a better understanding of brain development in both autistic and typical individuals.”
“The brain has been the ultimate black box. Here, the authors have used nerve cells derived from peripheral stem cells to peek inside this box. This important study suggests that this is possible and is deepening our understanding of autism,” Dr. Krystal added.
About this autism research article
Source: Elsevier Contacts: Rhiannon Bugno – Elsevier Image Source: The image is in the public domain.
Original Research: Open access “Atypical neurogenesis in induced pluripotent stem cell (iPSC) from autistic individuals” by Dwaipayan Adhya, Vivek Swarup, Roland Nagy, Lucia Dutan, Carole Shum, Eva Valencia-Alarcón, Kamila Maria Jozwik, Maria Andreina Mendez, Jamie Horder, Eva Loth, Paulina Nowosiad, Irene Lee, David Skuse, Frances Flinter, Declan Murphy, Grainne McAlonan, Daniel Geschwind, Jack Price, Jason Carroll, Deepak Srivastava, and Simon Baron-Cohen. Biological Psychiatry.
Atypical neurogenesis in induced pluripotent stem cell (iPSC) from autistic individuals
Background Autism is a heterogeneous collection of disorders with a complex molecular underpinning. Evidence from postmortem brain studies have indicated that early prenatal development may be altered in autism. Induced pluripotent stem cells (iPSCs) generated from individuals with autism with macrocephaly also indicate prenatal development as a critical period for this condition. But little is known about early altered cellular events during prenatal stages in autism.
Methods iPSCs were generated from 9 unrelated individuals with autism without macrocephaly and with heterogeneous genetic backgrounds, and 6 typically developing control individuals. iPSCs were differentiated toward either cortical or midbrain fates. Gene expression and high throughput cellular phenotyping was used to characterize iPSCs at different stages of differentiation.
Results A subset of autism-iPSC cortical neurons were RNA-sequenced to reveal autism-specific signatures similar to postmortem brain studies, indicating a potential common biological mechanism. Autism-iPSCs differentiated toward a cortical fate displayed impairments in the ability to self-form into neural rosettes. In addition, autism-iPSCs demonstrated significant differences in rate of cell type assignment of cortical precursors and dorsal and ventral forebrain precursors. These cellular phenotypes occurred in the absence of alterations in cell proliferation during cortical differentiation, differing from previous studies. Acquisition of cell fate during midbrain differentiation was not different between control- and autism-iPSCs.
Conclusions Taken together, our data indicate that autism-iPSCs diverge from control-iPSCs at a cellular level during early stage of neurodevelopment. This suggests that unique developmental differences associated with autism may be established at early prenatal stages.