Neuronal modeling of alternating hemiplegia of childhood reveals transcriptional compensation and replicates a trigger-induced phenotype

Snow, John P.; Westlake, Grant; Klofas, Lindsay K.; Jeon, Soyoun; Armstrong, Laura; Swoboda, Kathryn J.; George, Alfred L.; Ess, Kevin C.

doi:10.1016/j.nbd.2020.104881

Cited by 11 publications

(14 citation statements)

References 62 publications

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“…In other cases, the administration of commonly used drugs was not beneficial, or even deleterious [330,349]. These results do not necessarily invalidate the disease model, but can give insights about the cellular targets and the mechanisms of actions of these drugs.…”

Section: Use Of Meas In Phenotypic Rescue Experimentsmentioning

confidence: 81%

“…These results do not necessarily invalidate the disease model, but can give insights about the cellular targets and the mechanisms of actions of these drugs. For instance, Snow et al suggested that the inefficacy of treatment with flunarizine in improving the pathophysiological phenotype of hemiplegia of childhood (AHC) neuronal networks, might indicate that this drug, commonly used to prevent AHC episode, might exert an influence on other neuronal populations, such as GABAergic neurons, which were not present in their model [349].…”

Section: Use Of Meas In Phenotypic Rescue Experimentsmentioning

confidence: 99%

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The potential of in vitro neuronal networks cultured on micro electrode arrays for biomedical research

2023

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In vitro neuronal models have become an important tool to study healthy and diseased neuronal circuits. The growing interest of neuroscientists to explore the dynamics of neuronal systems and the increasing need to observe, measure and manipulate not only single neurons but populations of cells pushed for technological advancement. In this sense, Micro-Electrode Arrays (MEAs) emerged as a promising technique, made of cell culture dishes with embedded micro-electrodes allowing non-invasive and relatively simple measurement of the activity of neuronal cultures at the network level.In the past decade, MEAs popularity has rapidly grown. MEAs devices have been extensively used to measure the activity of neuronal cultures mainly derived from rodents. Rodent neuronal cultures on MEAs have been employed to investigate physiological mechanisms, study the effect of chemicals in neurotoxicity screenings, and model the electrophysiological phenotype of neuronal networks in different pathological conditions. With the advancements in human induced pluripotent stem cells (hiPSCs) technology, the differentiation of human neurons from the cells of adult donors became possible. hiPSCs-derived neuronal networks on MEAs have been employed to develop patient-specific in vitro platforms to characterize the pathophysiological phenotype and to test drugs, paving the way towards personalized medicine.In this review, we first describe MEAs technology and the information that can be obtained from MEAs recordings. Then, we give an overview of studies in which MEAs have been used in combination with different neuronal systems (i.e., rodent 2D and 3D neuronal cultures, organotypic brain slices, hiPSCs-derived 2D and 3D neuronal cultures, and brain organoids) for biomedical research, including physiology studies, neurotoxicity screenings, disease modeling, and drug testing. We end by discussing potential, challenges and future perspectives of MEAs technology, and providing some guidance for the choice of theneuronal model and MEAs device, experimental design, data analysis and reporting for scientific publications.

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Section: Use Of Meas In Phenotypic Rescue Experimentsmentioning

confidence: 81%

Section: Use Of Meas In Phenotypic Rescue Experimentsmentioning

confidence: 99%

The potential of in vitro neuronal networks cultured on micro electrode arrays for biomedical research

2023

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“…Dysfunction of NKA leads to increased excitability, marked dysfunction in GABA-ergic inhibition, and altered neuronal network physiology. [13][14][15][16] Clinical course of AHC has been described in three phases. Phase 1 is seen during first year of life in which there are predominant eye movement abnormalities, dystonic episodes, and some plegic attacks.…”

Section: Discussionmentioning

confidence: 99%

Alternating Hemiplegia of Childhood: A Series of Genetically Confirmed Four Cases from Southern India with Review of Published Literature

2020

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Alternating hemiplegia of childhood (AHC) is a rare autosomal dominant neurodevelopmental disorder with mutation on ATP1A3 gene. Delay in diagnosis and inappropriate diagnosis are common. We describe four genetically confirmed AHC patients to provide an improved understanding of the disorder. First symptom in two patients was seizures and in other two patients was abnormal eye deviation. All had onset of plegic attacks within the first 18 months of their life. Tone abnormalities and movement disorders were present in all patients. Electroencephalogram was abnormal in two patients and all had normal magnetic resonance imaging of the brain. Response to treatment of plegic attacks was poor and also epilepsy was drug resistant. All cases had significant development delay and disability as of last follow-up. Although there is no effective treatment so far, early diagnosis is required to avoid unnecessary treatment.

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“…Human Induced Pluripotent Stem Cell (hiPSC) Cell Culture: Two hiPSC lines (1) GM25256s from the Coriell Institute and (2) 77s from the Sahin lab (Sundberg et al, 2018) were cultured as previously described (Armstrong et al, 2017;Chalkley et al, 2022;Snow et al, 2020). In brief, iPSCs were grown as colonies on Matrigel (Corning, 354277) coated 6 well plates in mTeSR1 medium (StemCell Tech,85850) at 37°C and 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

Dephosphorylation of 4EBP1/2 Induces Prenatal Neural Stem Cell Quiescence

Geben

Brockman

Chalkley

et al. 2023

Preprint

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A limiting factor in the regenerative capacity of the adult brain is the abundance and proliferative ability of neural stem cells (NSCs). Adult NSCs are derived from a subpopulation of embryonic NSCs that temporarily enter quiescence during mid-gestation and remain quiescent until postnatal reactivation. Here we present evidence that the mechanistic/mammalian target of rapamycin (mTOR) pathway regulates quiescence entry in embryonic NSCs of the developing forebrain. Throughout embryogenesis, two downstream effectors of mTOR, p-4EBP1/2 T37/46 and p-S6 S240/244, were mutually exclusive in NSCs, rarely occurring in the same cell. While 4EBP1/2 was phosphorylated in stem cells undergoing mitosis at the ventricular surface, S6 was phosphorylated in more differentiated cells migrating away from the ventricle. Phosphorylation of 4EBP1/2, but not S6, was responsive to quiescence induction in cultured embryonic NSCs. Further, inhibition of p-4EBP1/2, but not p-S6, was sufficient to induce quiescence. Collectively, this work offers new insight into the regulation of quiescence entry in embryonic NSCs and, thereby, correct patterning of the adult brain. These data suggest unique biological functions of specific posttranslational modifications and indicate that the preferential inhibition of such modifications may be a useful therapeutic approach in neurodevelopmental diseases where NSC numbers, proliferation, and differentiation are altered.

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Neuronal modeling of alternating hemiplegia of childhood reveals transcriptional compensation and replicates a trigger-induced phenotype

Cited by 11 publications

References 62 publications

The potential of in vitro neuronal networks cultured on micro electrode arrays for biomedical research

The potential of in vitro neuronal networks cultured on micro electrode arrays for biomedical research

Alternating Hemiplegia of Childhood: A Series of Genetically Confirmed Four Cases from Southern India with Review of Published Literature

Dephosphorylation of 4EBP1/2 Induces Prenatal Neural Stem Cell Quiescence

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