Telencephalon Organoids Derived from an Individual with ADHD Show Altered Neurodevelopment of Early Cortical Layer Structure

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that occurs in early childhood and can persist to adulthood. It can affect many aspects of a patient's daily life, so it is necessary to explore the mechanism and pathological alterations. For this purpose, we applied induced pluripotent stem cell (iPSC)-derived telencephalon organoids to recapitulate the alterations occurring in the early cerebral cortex of ADHD patients. We found that telencephalon organoids of ADHD showed less growth of layer structures than control-derived organoids. On day 35 of differentiation, the thinner cortex layer structures of ADHD-derived organoids contained more neurons than those of control-derived organoids. Furthermore, ADHD-derived organoids showed a decrease in cell proliferation during development from day 35 to 56. On day 56 of differentiation, there was a significant difference in the proportion of symmetric and asymmetric cell division between the ADHD and control groups. In addition, we observed increased cell apoptosis in ADHD during early development. These results show alterations in the characteristics of neural stem cells and the formation of layer structures, which might indicate key roles in the pathogenesis of ADHD. Our organoids exhibit the cortical developmental alterations observed in neuroimaging studies, providing an experimental foundation for understanding the pathological mechanisms of ADHD. Graphical Abstract

Induced Pluripotent Stem Cells and Organoids in Advancing Neuropathology Research and Therapies

“…Specifically, the ADHD group exhibited reduced cell proliferation and differentiation, along with disparities in the proportion of symmetric and asymmetric cell division. These findings suggest that the observed alterations may play crucial roles in the pathogenesis of ADHD [105].…”

“…Telencephalon organoids derived from an individual with ADHD show altered neurodevelopment of early cortical layer structure [105] Model study ASD and ADHD iPSC Modeling human cerebellar development in vitro in 2D structure [243] Molecular study ADHD iPSC Generation of a human induced pluripotent stem cell (iPSC) line from a 51-year-old female with attention-deficit/hyperactivity disorder (ADHD) carrying a duplication of SLC2A3 [244] Model study ADHD iPSC Generation of four iPSC lines from peripheral blood mononuclear cells (PBMCs) of an attention-deficit/hyperactivity disorder (ADHD) individual and a healthy sibling in a Caucasian family in Australia [245] Model study ADHD iPSCs and NSCs Growth rates of human induced pluripotent stem cells and neural stem cells from attention-deficit/hyperactivity disorder patients: a preliminary study [246] Molecular study HD iPSC…”

Loss ofUBE3Aimpacts both neuronal and non-neuronal cells in human cerebral organoids

“…This may connect to observations of microcephaly in AS (albeit a phenotype with incomplete penetrance), as well as to potential imbalances in neuronal subtypes that might affect relative excitatory and inhibitory signaling. Models of other neurodevelopmental disorders have also reported altered organoid compositions 34,65 . Our results suggest UBE3A helps support neural stem and progenitor proliferation potentially through impacts on cell cycle progression.…”

hiPSC-derived cortical neurons from ADHD individuals reveal dysregulated glutamatergic development

“…A recent study by Yde Ohki et al was able to identify proliferation rate alterations in hiPSC-derived neural stem cells derived from male child and adolescent ADHD patients 28 . Lastly, a study using hiPSC-derived telencephalon brain organoids from one healthy control and one ADHD patient reported thinner cortex layers in ADHD organoids 29 .…”