Cerebral organoids reveal early cortical maldevelopment in schizophrenia—computational anatomy and genomics, role of FGFR1

Abstract

Studies of induced pluripotent stem cells (iPSCs) from schizophrenia patients and control individuals revealed that the disorder is programmed at the preneuronal stage, involves a common dysregulated mRNA transcriptome, and identified Integrative Nuclear FGFR1 Signaling a common dysregulated mechanism. We used human embryonic stem cell (hESC) and iPSC-derived cerebral organoids from four controls and three schizophrenia patients to model the first trimester of in utero brain development. The schizophrenia organoids revealed an abnormal scattering of proliferating Ki67+ neural progenitor cells (NPCs) from the ventricular zone (VZ), throughout the intermediate (IZ) and cortical (CZ) zones. TBR1 pioneer neurons and reelin, which guides cortico-petal migration, were restricted from the schizophrenia cortex. The maturing neurons were abundantly developed in the subcortical regions, but were depleted from the schizophrenia cortex. The decreased intracortical connectivity was denoted by changes in the orientation and morphology of calretinin interneurons. In schizophrenia organoids, nuclear (n)FGFR1 was abundantly expressed by developing subcortical cells, but was depleted from the neuronal committed cells (NCCs) of the CZ. Transfection of dominant negative and constitutively active nFGFR1 caused widespread disruption of the neuro-ontogenic gene networks in hESC-derived NPCs and NCCs. The fgfr1 gene was the most prominent FGFR gene expressed in NPCs and NCCs, and blocking with PD173074 reproduced both the loss of nFGFR1 and cortical neuronal maturation in hESC cerebral organoids. We report for the first time, progression of the cortical malformation in schizophrenia and link it to altered FGFR1 signaling. Targeting INFS may offer a preventive treatment of schizophrenia.

‘Phase Zero’ clinical study platform combining broadband Vis/near-infrared spectroscopy and electrophysiology to study human brain organoid models of neurodevelopmental disorders

“…Our cerebral organoid studies using induced pluripotent stem cells (iPSCs) from schizophrenia patients and healthy control individuals revealed improperly clustered immature neurons in cortical layers II, III, and V and decreased intracortical connectivity with disrupted orientation and morphology of calretinin interneurons 8 -a subpopulation of GABAergic cells. Since the GABAergic inhibitory cells locally control the activity of numerous excitatory principal cells, so they maintain local excitation-inhibition (E-I) balance 11 .…”

“…Here, any runaway excitation or quiescence can lead to abnormal regulation of the E-I balance, which can lead to nervous system disorders, including schizophrenia 7 . In fact, in-utero brain development has been implicated in the pathophysiology of schizophrenia 8 ; however, the first symptoms of schizophrenia manifest only in early adulthood 9 . Recent works have shown that brain organoid models can provide an understanding of the fundamental features of in-utero neurodevelopment in health and disease 10 .…”

Stem Cells, Genome Editing, and the Path to Translational Medicine

“…Organoid models are now a common tool to study neurodevelopmental disorders, including microcephaly (Lancaster et al, 2013; Li et al, 2017a), autism spectrum disease associated with macrocephaly (Mariani et al, 2017; Wang et al, 2017), lissencephally (Bershteyn et al, 2017; Karzbrun et al, 2018), Rett Syndrom (Mellios et al, 2017), Thymothy syndrome (Birey et al, 2017), lysosomal storage diseases such as Sandhoff disease (Allende et al, 2018), schizophrenia (Srikanth et al, 2018; Stachowiak et al, 2017) and Zika infection on neonatal brain development (reviewed in (Qian et al, 2017). Despite the early success with this approach for disease-modelling, challenges remain.…”

Bioenergy Crisis in Coronavirus Diseases?

“…Recent data shows that FGF21 protects against hypoxia stress-induced injury in the cerebral microvascular endothelial cells [22]. So, FGF signaling can have a protective role not only in hypoxia-related brain disorders, e.g., encephalopathy, but also in neurodevelopmental disorders, e.g., schizophrenia [23], due to prenatal immune insult [24]. Without quantitative brain monitoring of the neuroenergetics and the functional genomics, deeper understanding of the early neurovascular signs of SAE will remain unfulfilled that is important for triaging and for tailoring the therapies.…”

“…Figure 1 shows the experimental setup where a 32-channel 3D microelectrode array (MEA) based electrophysiological (Ephys) recording was combined with the broadband Vis-NIR spectroscopy of the activity of the mitochondrial Electron Transport Chain (ETC) complexes. Also, computational anatomy and functional genomics were performed on the organoids [23] that are proposed to investigate genetic mechanisms underlying brain susceptibility to cytokine storms [19] and bioenergy crisis. spectroscopy [35] to monitor the neuronal as well as neurometabolic coupling state in the microgliacontaining cerebral-vascular organoids.…”