From cells to insights: the power of human pluripotent stem cell-derived cortical interneurons in psychiatric disorder modeling.

Psychiatric disorders, such as schizophrenia (SCZ) and autism spectrum disorders (ASD), represent a global health challenge with their poorly understood and complex etiologies. Cortical interneurons (cINs) are the primary inhibitory neurons in the cortex and their subtypes, especially those that are generated from the medial ganglionic emission (MGE) region, have been shown to play an important role in the pathogenesis of these psychiatric disorders. Recent advances in induced pluripotent stem cell (iPSC) technologies provide exciting opportunities to model and study these disorders using human iPSC-derived cINs.

Generation of Homogeneous Populations of Cortical Interneurons from Human Pluripotent Stem Cells.

Cortical interneurons (cINs), especially those that are derived from the medial ganglionic eminence (MGE) during early development, are associated with various neuropsychiatric disorders. Human pluripotent stem cell (hPSC)-derived cINs can provide unlimited cell sources for studying disease mechanisms and developing novel therapeutics. Here, we describe an optimized method to generate homogeneous cIN populations based on three-dimensional (3D) cIN sphere generation.

YBX1-Mediated DNA Methylation-Dependent SHANK3 Expression in PBMCs and Developing Cortical Interneurons in Schizophrenia.

Schizophrenia (SCZ) is a severe psychiatric and neurodevelopmental disorder. The pathological process of SCZ starts early during development, way before the first onset of psychotic symptoms. DNA methylation plays an important role in regulating gene expression and dysregulated DNA methylation is involved in the pathogenesis of various diseases.

Human cortical interneurons optimized for grafting specifically integrate, abort seizures, and display prolonged efficacy without over-inhibition.

Previously, we demonstrated the efficacy of human pluripotent stem cell (hPSC)-derived GABAergic cortical interneuron (cIN) grafts in ameliorating seizures. However, a safe and reliable clinical translation requires a mechanistic understanding of graft function, as well as the assurance of long-term efficacy and safety. By employing hPSC-derived chemically matured migratory cINs in two models of epilepsy, we demonstrate lasting efficacy in treating seizures and comorbid deficits, as well as safety without uncontrolled growth.

Generation of neural organoids for spinal-cord regeneration via the direct reprogramming of human astrocytes.

Organoids with region-specific architecture could facilitate the repair of injuries of the central nervous system. Here we show that human astrocytes can be directly reprogrammed into early neuroectodermal cells via the overexpression of OCT4, the suppression of p53 and the provision of the small molecules CHIR99021, SB431542, RepSox and Y27632. We also report that the activation of signalling mediated by fibroblast growth factor, sonic hedgehog and bone morphogenetic protein 4 in the reprogrammed cells induces them to form spinal-cord organoids with functional neurons specific to the dorsal and ventral domains.

Mitochondrial dysfunction in psychiatric disorders.

Psychiatric disorders are a heterogeneous group of mental disorders with abnormal mental or behavioral patterns, which severely distress or disable affected individuals and can have a grave socioeconomic burden. Growing evidence indicates that mitochondrial function plays an important role in developing psychiatric disorders. This review discusses the neuropsychiatric consequences of mitochondrial abnormalities in both animal models and patients.

Impact of schizophrenia GWAS loci converge onto distinct pathways in cortical interneurons vs glutamatergic neurons during development.

Remarkable advances have been made in schizophrenia (SCZ) GWAS, but gleaning biological insight from these loci is challenging. Genetic influences on gene expression (e.g.

Migratory cortical interneuron-specific transcriptome abnormalities in schizophrenia.

Cortical interneurons (cINs) are substantially affected in Schizophrenia (SCZ) and enriched for SCZ heritability during development. To understand SCZ-specific changes in these cells during development, we isolated migratory cINs from cIN spheres derived from 5 healthy control (HC) and 5 SCZ induced pluripotent stem cell lines (iPSCs). Transcriptome analyses show dysregulation in extracellular matrix pathways as the major disturbances in SCZ migratory cINs, whereas sphere cINs show dysregulation in immune pathways.

Activated microglia cause metabolic disruptions in developmental cortical interneurons that persist in interneurons from individuals with schizophrenia.

The mechanisms by which prenatal immune activation increase the risk for neuropsychiatric disorders are unclear. Here, we generated developmental cortical interneurons (cINs)-which are known to be affected in schizophrenia (SCZ) when matured-from induced pluripotent stem cells (iPSCs) derived from healthy controls (HCs) and individuals with SCZ and co-cultured them with or without activated microglia. Co-culture with activated microglia disturbed metabolic pathways, as indicated by unbiased transcriptome analyses, and impaired mitochondrial function, arborization, synapse formation and synaptic GABA release.

Human forebrain endothelial cell therapy for psychiatric disorders.

Abnormalities of or reductions in GABAergic interneurons are implicated in the pathology of severe neuropsychiatric disorders, for which effective treatments are still elusive. Transplantation of human stem cell-derived interneurons is a promising cell-based therapy for treatment of these disorders. In mouse xenograft studies, human stem cell-derived-interneuron precursors could differentiate in vivo, but required a prolonged time of four to seven months to migrate from the graft site and integrate with the host tissue.

Mitochondrial Dysfunction in Schizophrenia.

Schizophrenia (SCZ) is a severe neurodevelopmental disorder affecting 1% of populations worldwide with a grave disability and socioeconomic burden. Current antipsychotic medications are effective treatments for positive symptoms, but poorly address negative symptoms and cognitive symptoms, warranting the development of better treatment options. Further understanding of SCZ pathogenesis is critical in these endeavors.

Correction: iPSC-derived homogeneous populations of developing schizophrenia cortical interneurons have compromised mitochondrial function.

A correction to this paper has been published and can be accessed via a link at the top of the paper.

Large-Scale Generation and Characterization of Homogeneous Populations of Migratory Cortical Interneurons from Human Pluripotent Stem Cells.

During development, cortical interneurons (cINs) are generated from the ventral telencephalon, robustly migrate to the dorsal telencephalon, make local synaptic connections, and critically regulate brain circuitry by inhibiting other neurons. Thus, their abnormality is associated with various brain disorders. Human pluripotent stem cell (hPSC)-derived cINs can provide unlimited sources with which to study the pathogenesis mechanism of these disorders as well as provide a platform to develop novel therapeutics.

iPSC-derived homogeneous populations of developing schizophrenia cortical interneurons have compromised mitochondrial function.

Schizophrenia (SCZ) is a neurodevelopmental disorder. Thus, studying pathogenetic mechanisms underlying SCZ requires studying the development of brain cells. Cortical interneurons (cINs) are consistently observed to be abnormal in SCZ postmortem brains.

Dysregulated protocadherin-pathway activity as an intrinsic defect in induced pluripotent stem cell-derived cortical interneurons from subjects with schizophrenia.

We generated cortical interneurons (cINs) from induced pluripotent stem cells derived from 14 healthy controls and 14 subjects with schizophrenia. Both healthy control cINs and schizophrenia cINs were authentic, fired spontaneously, received functional excitatory inputs from host neurons, and induced GABA-mediated inhibition in host neurons in vivo. However, schizophrenia cINs had dysregulated expression of protocadherin genes, which lie within documented schizophrenia loci.

Cortical GABAergic Interneuron/Progenitor Transplantation as a Novel Therapy for Intractable Epilepsy.

Epilepsy is a severe neurological disease affecting more than 70 million people worldwide that is characterized by unpredictable and abnormal electrical discharges resulting in recurrent seizures. Although antiepileptic drugs (AEDs) are the mainstay of epilepsy treatment for seizure control, about one third of patients with epilepsy suffer from intractable seizures that are unresponsive to AEDs. Furthermore, the patients that respond to AEDs typically experience adverse systemic side effects, underscoring the urgent need to develop new therapies that target epileptic foci rather than more systemic interventions.

Modeling schizophrenia pathogenesis using patient-derived induced pluripotent stem cells (iPSCs).

Schizophrenia is a chronic disabling mental disorder that affects about 1% population world-wide, for which there is a desperate need to develop more effective treatments. In this minireview, we summarize the findings from recent studies using induced pluripotent stem cells to model the developmental pathogenesis of schizophrenia and discuss what we have learned from these studies. We also discuss what are the important next steps and key issues to be addressed to move the field forward.

Effects of shoulder reaching exercise on the balance of patients with hemiplegia after stroke.

[Purpose] This study investigated whether a shoulder reaching exercise was beneficial for restoring the standing balance of patients with hemiplegia after stroke. [Subjects and Methods] There were 13 subjects in the experimental group (EG) and 14 subjects in the control group (CG), all with hemiplegia following stroke. The shoulder reaching exercise intervention was performed by the EG and conventional physical therapy was administered to the CG for 30 minutes, 3 times a week for 4 weeks.

The effect of co-stabilizer muscle activation on knee joint position sense: a single group pre-post test.

[Purpose] The purpose of this study was to investigate the effect of co-stabilizer muscle activation on knee joint position sense. [Subjects and Methods] This study was a pre-post, single-blinded randomly controlled trial (angle sequence randomly selected) design. Seven healthy adults with no orthopaedic or neurological problems participated in this study.

Severe Endobronchial Inflammation Induced by Aspiration of a Ferrous Sulfate Tablet.

Iron supplements such as ferrous sulfate tablets are usually used to treat iron-deficiency anemia in some elderly patients with primary neurologic disorders or decreased gag reflexes due to stroke, senile dementia, or parkinsonism. While the aspiration of ferrous sulfate is rarely reported, it is a potentially life-threatening condition that can lead to airway necrosis and bronchial stenosis. A detailed history and high suspicion of aspiration are required to avoid delays in diagnosis and treatment.

Differentiation of human pluripotent stem cells into Medial Ganglionic Eminence vs. Caudal Ganglionic Eminence cells.

Human pluripotent stem cells (PSCs) represent an opportunity to study human development in vitro, to model diseases in a dish, to screen drugs as well as to provide an unlimited and ethically unimpeded source of therapeutic cells. Cortical GABAergic interneurons, which are generated from Medial Ganglionic Eminence (MGE) cells and Caudal Ganglionic Eminence (CGE) cells during embryonic development, regulate cortical neural networks by providing inhibitory inputs. Their malfunction, resulting in failure to intricately regulate neural circuit balance, has been implicated in brain diseases, such as schizophrenia, autism and epilepsy.

Optimization of pilocarpine-mediated seizure induction in immunodeficient NodScid mice.

Temporal lobe epilepsy (TLE) has been modeled in mice using pilocarpine induction, with variable results depending on specific strains. To allow efficient xenotransplantation for the purpose of optimizing potential cell-based therapy of human TLE, we have determined the optimal dosing strategy to produce spontaneous recurring seizures in immunodeficient NodScid mice. Multiple 100mg/kg injections of pilocarpine have been shown to be more effective than single 300-400mg/kg injections for inducing spontaneous seizures in NodScid mice.

hPSC-derived maturing GABAergic interneurons ameliorate seizures and abnormal behavior in epileptic mice.

Seizure disorders debilitate more than 65,000,000 people worldwide, with temporal lobe epilepsy (TLE) being the most common form. Previous studies have shown that transplantation of GABA-releasing cells results in suppression of seizures in epileptic mice. Derivation of interneurons from human pluripotent stem cells (hPSCs) has been reported, pointing to clinical translation of quality-controlled human cell sources that can enhance inhibitory drive and restore host circuitry.

Improvement of neurological dysfunctions in aphakia mice, a model of Parkinson's disease, after transplantation of ES cell-derived dopaminergic neuronal precursors.

Parkinson's disease (PD) is characterized by selective death of the substantia nigra dopaminergic neurons, and previously we have shown that aphakia mice, which harbor spontaneous Pitx3 gene mutation, show specific degeneration of the substantia nigra dopaminergic neurons accompanied by behavioral deficits that is reversed by L-DOPA treatment or transplantation of dopaminergic neural precursors. Here, we describe transplantation of dopaminergic neural precursors to a mouse model of PD, an aphakia mouse, followed by behavioral analyses of transplanted mice.