| 1. |
- Izsak, Julia, et al.
(författare)
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Case report: Olanzapine-associated water retention, high blood pressure, and subsequent preterm preeclampsia.
- 2023
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Ingår i: Frontiers in psychiatry. - 1664-0640. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Olanzapine is one of the most frequently used antipsychotic medications during pregnancy, but information about its safety and adverse effects profile during pregnancy is scarce. We herein describe a case of a pregnant woman with several psychiatric disorders who developed water retention, hypertension, and subsequent preterm preeclampsia 3weeks after initiation of treatment with olanzapine. To the best of our knowledge, this is the first case of olanzapine-associated preeclampsia described in literature.
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| 2. |
- Izsak, Julia, et al.
(författare)
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Differential acute impact of therapeutically effective and overdose concentrations of lithium on human neuronal single cell and network function
- 2021
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Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Lithium salts are used as mood-balancing medication prescribed to patients suffering from neuropsychiatric disorders, such as bipolar disorder and major depressive disorder. Lithium salts cross the blood-brain barrier and reach the brain parenchyma within few hours after oral application, however, how lithium influences directly human neuronal function is unknown. We applied patch–clamp and microelectrode array technology on human induced pluripotent stem cell (iPSC)-derived cortical neurons acutely exposed to therapeutic (<1 mM) and overdose concentrations (>1 mM) of lithium chloride (LiCl) to assess how therapeutically effective and overdose concentrations of LiCl directly influence human neuronal electrophysiological function at the synapse, single-cell, and neuronal network level. We describe that human iPSC-cortical neurons exposed to lithium showed an increased neuronal activity under all tested concentrations. Furthermore, we reveal a lithium-induced, concentration-dependent, transition of regular synchronous neuronal network activity using therapeutically effective concentration (<1 mM LiCl) to epileptiform-like neuronal discharges using overdose concentration (>1 mM LiCl). The overdose concentration lithium-induced epileptiform-like activity was similar to the epileptiform-like activity caused by the GABAA-receptor antagonist. Patch–clamp recordings reveal that lithium reduces action potential threshold at all concentrations, however, only overdose concentration causes increased frequency of spontaneous AMPA-receptor mediated transmission. By applying the AMPA-receptor antagonist and anti-epileptic drug Perampanel, we demonstrate that Perampanel suppresses lithium-induced epileptiform-like activity in human cortical neurons. We provide insights in how therapeutically effective and overdose concentration of lithium directly influences human neuronal function at synapse, a single neuron, and neuronal network levels. Furthermore, we provide evidence that Perampanel suppresses pathological neuronal discharges caused by overdose concentrations of lithium in human neurons.
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| 3. |
- Izsak, Julia, et al.
(författare)
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Human Cerebrospinal Fluid Promotes Neuronal Circuit Maturation of Human Induced Pluripotent Stem Cell-Derived 3D Neural Aggregates
- 2020
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Ingår i: Stem Cell Reports. - : Elsevier BV. - 2213-6711. ; 14:6, s. 1044-1059
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Tidskriftsartikel (refereegranskat)abstract
- Human induced pluripotent stem cell (hiPSC)-derived in vitro neural and organoid models resemble fetal, rather than adult brain properties, indicating that currently applied cultivation media and supplements are insufficient to achieve neural maturation beyond the fetal stage. In vivo, cerebrospinal fluid molecules are regulating the transition of the immature fetal human brain into a mature adult brain. By culturing hiPSC-3D neural aggregates in human cerebrospinal fluid (hCSF) obtained from healthy adult individuals, we demonstrate that hCSF rapidly triggers neurogenesis, gliogenesis, synapse formation, neurite outgrowth, suppresses proliferation of residing neural stem cells, and results in the formation of synchronously active neuronal circuits in vitro within 3 days. Thus, a physiologically relevant and adult brain-like milieu triggers maturation of hiPSC-3D neural aggregates into highly functional neuronal circuits in vitro. The approach presented here opens a new avenue to identify novel physiological factors for the improvement of hiPSC neural in vitro models.
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| 4. |
- Izsak, Julia
(författare)
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Human iPSC-derived neuronal networks. Development and application for compound evaluation
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Research on human brain development and function in health and disease has been hampered by limited access to primary human tissue and limited translatability of animal studies. This knowledge gap is encouraging the use of human induced pluripotent stem cell (hiPSC)-derived neural in vitro models. The current hope is that person-specific hiPSC-based in vitro models for human brain development and neuronal network function will increase the success in translating research results from bench to bedside. The aim of this thesis was to characterize and validate a person-specific human iPSC-based neural in vitro model to study the development, properties, and pharmacological modulation of human neuronal networks. In the first article we presented a procedure to generate 3D neural aggregates comprising astrocytes, oligodendrocytes and highly functional neurons that generated synchronous neuronal networks in less than three weeks. Further, by culturing hiPSC-derived 3D neural aggregates in human cerebrospinal fluid (hCSF), we demonstrated in article II that this adult brain-like milieu promotes morphological and functional maturation. Although hCSF is superior to currently used cell culture media, it has very limited availability for routine cell culturing purposes. This motivated the search for soluble factors that can mimic the observed maturational effects. In article III, we identified TGF-β1 as a physiologically relevant factor that can suppress proliferation and enhance neuronal and glial differentiation in a human 3D neural in vitro model. In article IV, we utilized this optimized model to provide insights in how therapeutically effective and overdose concentrations of lithium influence human single neuronal and network function. We showed that epileptiform discharges caused by overdose concentrations of lithium were suppressed by the antiepileptic drug Perampanel. The demonstrated functional impact of clinically relevant pharmacological compounds on human neuronal network function represents a proof-of-concept for the enhanced translational value of the human 3D neural aggregate in vitro model. The work presented in this thesis advances the field with a fast functional isogenic in vitro hiPSC-derived neuronal network model with improved physiological relevance and applicability for drug evaluation. Hopefully, our findings will bring the field of neuroscience closer to more translatable modeling and more successful clinical trials in the future.
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| 5. |
- Izsak, Julia, et al.
(författare)
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Robust generation of person-specific, synchronously active neuronal networks using purely isogenic human iPSC-3D neural aggregate cultures
- 2019
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Ingår i: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-4548 .- 1662-453X. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Reproducibly generating human induced pluripotent stem cell-based functional neuronal circuits, solely obtained from single individuals, poses particular challenges to achieve personalized and patient specific functional neuronal in vitro models. A hallmark of functional neuronal assemblies, synchronous neuronal activity, can be non-invasively studied by microelectrode array (MEA) technology, reliably capturing physiological and pathophysiological aspects of human brain function. In our here presented manuscript, we demonstrate a procedure to generate 3D neural aggregates comprising astrocytes, oligodendroglial cells, and neurons obtained from the same human tissue sample. Moreover, we demonstrate the robust ability of those neurons to create a highly synchronously active neuronal network within 3 weeks in vitro, without additionally applied astrocytes. The fusion of MEA-technology with functional neuronal circuits solely obtained from one individual's cells represent isogenic person-specific human neuronal sensor chips that pave the way for specific personalized in vitro neuronal networks as well as neurological and neuropsychiatric disease modeling.
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| 6. |
- Izsak, Julia, et al.
(författare)
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TGF-β1 Suppresses Proliferation and Induces Differentiation in Human iPSC Neural in vitro Models
- 2020
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Ingår i: Frontiers in Cell and Developmental Biology. - : Frontiers Media SA. - 2296-634X. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Persistent neural stem cell (NSC) proliferation is, among others, a hallmark of immaturity in human induced pluripotent stem cell (hiPSC)-based neural models. TGF-β1 is known to regulate NSCs in vivo during embryonic development in rodents. Here we examined the role of TGF-β1 as a potential candidate to promote in vitro differentiation of hiPSCs-derived NSCs and maturation of neuronal progenies. We present that TGF-β1 is specifically present in early phases of human fetal brain development. We applied confocal imaging and electrophysiological assessment in hiPSC-NSC and 3D neural in vitro models and demonstrate that TGF-β1 is a signaling protein, which specifically suppresses proliferation, enhances neuronal and glial differentiation, without effecting neuronal maturation. Moreover, we demonstrate that TGF-β1 is equally efficient in enhancing neuronal differentiation of human NSCs as an artificial synthetic small molecule. The presented approach provides a proof-of-concept to replace artificial small molecules with more physiological signaling factors, which paves the way to improve the physiological relevance of human neural developmental in vitro models.
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