Developmental excitation-inhibition imbalance underlying psychoses revealed by single-cell analyses of discordant twins-derived cerebral organoids

Abstract

Despite extensive genetic and neuroimaging studies, detailed cellular mechanisms underlying schizophrenia and bipolar disorder remain poorly understood. Recent progress in single-cell RNA sequencing (scRNA-seq) technologies enables identification of cell-type-specific pathophysiology. However, its application to psychiatric disorders is challenging because of methodological difficulties in analyzing human brains and the confounds due to a lifetime of illness. Brain organoids derived from induced pluripotent stem cells (iPSCs) of the patients are a powerful avenue to investigate the pathophysiological processes. Here, we generated iPSC-derived cerebral organoids from monozygotic twins discordant for psychosis. scRNA-seq analysis of the organoids revealed enhanced GABAergic specification and reduced cell proliferation following diminished Wnt signaling in the patient, which was confirmed in iPSC-derived forebrain neuronal cells. Two additional monozygotic twin pairs discordant for schizophrenia also confirmed the excess GABAergic specification of the patients’ neural progenitor cells. With a well-controlled genetic background, our data suggest that unbalanced specification of excitatory and inhibitory neurons during cortical development underlies psychoses.

Catatonia associated with late-life psychosis successfully treated with lithium: a case report

“…A previous study, using induced pluripotent stem cells (iPSCs) derived from neuronal cells of patients with bipolar disorders, has reported that the hyperexcitability phenotype of young neurons was selectively reversed by lithium only in lithium responders [ 21 ]. Moreover, a recent study using iPSCs derived from monozygotic twins discordant for major psychosis has suggested that lithium may normalize unbalanced specification of excitatory and inhibitory neurons in major psychosis neural circuits, by activating the Wnt signaling pathway [ 22 ]. In the present case of catatonia associated with late-life psychosis, lithium, although not as fast-acting as ECT, was effective for both catatonic and psychotic symptoms, as it normalized unbalanced specification of excitatory and inhibitory systems in the brain.…”

Expression bias in retinoic acid responsive genes defines variations in neural differentiation of human pluripotent stem cells

“…The exploration of how and when these stable expression phenotypes and corresponding lineage-predisposing states are generated and stably set in vivo and in vitro will enable a deeper understanding of human variation and further the discovery potential of hPSCs. The genetics of neurodevelopmental disorders (Deneault et al, 2018; Klaus et al, 2019; Paulsen et al, 2020; Sawada et al, 2020) and human brain evolution (Kanton et al, 2019; Mora-Bermudez et al, 2016; Pollen et al, 2019; Trujillo et al, 2021) are being integrated into cerebral organoid models that parallel in utero and early postnatal brain development (Gordon et al, 2021; Trevino et al, 2020). The developmental perspectives we put forward here will inform molecular phenotyping and assay development as these in vitro models of brain development become increasingly complex and the implications of distant endpoint assays more uncertain.…”

Catatonia Associated With Late Paraphrenia Successfully Treated With Lithium: A Case Report

“…A previous study, using induced pluripotent stem cells (iPSCs) derived from neuronal cells of patients with bipolar disorders, has reported that the hyperexcitability phenotype of young neurons was selectively reversed by lithium only in lithium responders [21]. Moreover, a recent study using iPSCs derived from monozygotic twins discordant for major psychosis has suggested that lithium may normalize unbalanced speci cation of excitatory and inhibitory neurons in major psychosis neural circuits, by activating the Wnt signaling pathway [22]. In the present case of catatonia associated with late paraphrenia, lithium, although not as fast-acting as ECT, was effective for both catatonic and psychotic symptoms, as it normalized unbalanced speci cation of excitatory and inhibitory systems in the brain.…”