Identification of neural oscillations and epileptiform changes in human brain organoids

Abstract

Brain organoids represent a powerful tool for studying human neurological diseases, particularly those impacting brain growth and structure. However, many diseases manifest with clear evidence of physiological and network abnormality in the absence of anatomical changes, raising the question of whether organoids possess sufficient neural network complexity to model these conditions. Here, we explore the network level functions of brain organoids using calcium sensor imaging and extracellular recording approaches that together reveal the existence of complex network dynamics reminiscent of intact brain preparations. We demonstrate highly abnormal and epileptiform-like activity in organoids derived from Rett syndrome patient induced pluripotent stem cells accompanied by transcriptomic differences revealed by single-cell analyses. We also rescue key physiological activities with an unconventional neuroregulatory drug, Pifithrin-a.Together, these findings provide an essential foundation for the utilization of brain organoids to study intact and disordered human brain network formation and illustrate their utility in therapeutic discovery.

Paving Therapeutic Avenues for FOXG1 Syndrome: Untangling Genotypes and Phenotypes from a Molecular Perspective

“…The severity of the phenotypic alterations upon impaired FOXG1 expression correlated directly with the remaining dose of FOXG1 in the cells, emphasising that a well-balanced availability of the FOXG1 protein is critical for proper brain development and function [63]. But still, whereas Rett syndrome patient-derived hiPSCs were differentiated into organoids [64], [65], this experimental approach is thus far not reported for hiPSCs of FOXG1 patients. Overall, there are now opportunities for investigating FOXG1 syndrome in hiPSCs and different types of organoids, e.g.…”

In Vitro Recapitulation of Neuropsychiatric Disorders with Pluripotent Stem Cells-Derived Brain Organoids

“…Although confronting with sorts of technical obstacles, we still can make full use of the human brain organoid model combining with new technologies to investigate the neuropsychiatric disorders. At the beginning stage as PSCs, through combining with CRISPR-mediated genomic engineering, isogenic comparisons of PSCs with various identities caused by psychiatric disorder-associated variants could be generated and these genetically modified PSCs derived brain organoids could be applied to elucidate the detailed mechanism between different variants [ 81 , 82 ]. During cultivation process, artificially designed synthetic materials with more accordant compositions could be used as scaffolds to elevate the reproducibility and generate organoids with standard shapes and sizes [ 80 ].…”

Human brain organoid networks

“…Under a variety of conditions 1 , 3D assemblies of pluripotent stem cells can differentiate into a wide diversity of brain cell types and assume certain anatomical features that resemble the developing brain as well as some mature features such as dendritic spines, inhibitory and excitatory synapses [2][3][4] with presynaptic vesicles 5 . Neurons within these 3D assemblies generate action potentials upon depolarization 6 , display excitatory and inhibitory post synaptic currents 7 and exhibit spontaneous network activity as measured by calcium imaging 6,[8][9][10] and by extracellular field potential recordings from a small number of electrodes 5,[11][12][13][14] . Progress in the development of flexible electronics have also enabled three-dimensional readout of electrical activity across the surface of an organoid 15 , and recent work has extended the activity repertoire of organoids to include rhythmic activity over a range of oscillatory frequencies 10,16 .…”

“…Neurons within these 3D assemblies generate action potentials upon depolarization 6 , display excitatory and inhibitory post synaptic currents 7 and exhibit spontaneous network activity as measured by calcium imaging 6,[8][9][10] and by extracellular field potential recordings from a small number of electrodes 5,[11][12][13][14] . Progress in the development of flexible electronics have also enabled three-dimensional readout of electrical activity across the surface of an organoid 15 , and recent work has extended the activity repertoire of organoids to include rhythmic activity over a range of oscillatory frequencies 10,16 . However, technological limitations have restricted broadband detection of electrical activity to small numbers of neurons.…”