Single-cell and neuronal network alterations in an <i>in vitro</i> model of Fragile X syndrome

Moskalyuk, A. A.; Kooy, Frank; Giugliano, Michèle

doi:10.1101/366997

Cited by 4 publications

(4 citation statements)

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“…Increased burst frequency has been reported in mouse Fmr1 −/y somatosensory cortical neurons [12] and Fmr1 −/y neurons in mouse cortical primary cultures [53]. However, the vast majority of neurons in our cultures are glutamatergic since there are no GABAergic interneurons, as assessed by staining for GAD [27][28][29].…”

Section: Limitationsmentioning

confidence: 50%

Cortical neurons derived from human pluripotent stem cells lacking FMRP display altered spontaneous firing patterns

et al. 2020

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Background: Fragile X syndrome (FXS), a neurodevelopmental disorder, is a leading monogenetic cause of intellectual disability and autism spectrum disorder. Notwithstanding the extensive studies using rodent and other pre-clinical models of FXS, which have provided detailed mechanistic insights into the pathophysiology of this disorder, it is only relatively recently that human stem cell-derived neurons have been employed as a model system to further our understanding of the pathophysiological events that may underlie FXS. Our study assesses the physiological properties of human pluripotent stem cell-derived cortical neurons lacking fragile X mental retardation protein (FMRP). Methods: Electrophysiological whole-cell voltage-and current-clamp recordings were performed on two control and three FXS patient lines of human cortical neurons derived from induced pluripotent stem cells. In addition, we also describe the properties of an isogenic pair of lines in one of which FMR1 gene expression has been silenced. Results: Neurons lacking FMRP displayed bursts of spontaneous action potential firing that were more frequent but shorter in duration compared to those recorded from neurons expressing FMRP. Inhibition of large conductance Ca 2+activated K + currents and the persistent Na + current in control neurons phenocopies action potential bursting observed in neurons lacking FMRP, while in neurons lacking FMRP pharmacological potentiation of voltage-dependent Na + channels phenocopies action potential bursting observed in control neurons. Notwithstanding the changes in spontaneous action potential firing, we did not observe any differences in the intrinsic properties of neurons in any of the lines examined. Moreover, we did not detect any differences in the properties of miniature excitatory postsynaptic currents in any of the lines. Conclusions: Pharmacological manipulations can alter the action potential burst profiles in both control and FMRPnull human cortical neurons, making them appear like their genetic counterpart. Our studies indicate that FMRP targets that have been found in rodent models of FXS are also potential targets in a human-based model system, and we suggest potential mechanisms by which activity is altered.

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Section: Limitationsmentioning

confidence: 50%

Cortical neurons derived from human pluripotent stem cells lacking FMRP display altered spontaneous firing patterns

et al. 2020

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“…Dissociated neurons served as a model for studying the progression of neuronal disorders. In a recent study (39), neurons dissociated from a mouse model of Fragile X syndrome (Fmr1 KO) were recorded by means of microelectrode arrays (MEAs) from 7 to 35 DIV, and exhibited an abnormally increased synchronization of spontaneous firing events at mature stages. Moreover, they showed oscillations in the beta frequency range, which were not observed in controls.…”

Section: "Traditional" Dissociated Cultures -Methods Applications and Spontaneous Activitymentioning

confidence: 99%

Evaluation of in vitro neuronal networks for the study of spontaneous activity

Pozzi

2020

STEMedicine

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In the absence of external stimuli, the nervous system exhibits a spontaneous electrical activity whose functions are not fully understood, and that represents the background noise of brain operations. Spontaneous activity has been proven to arise not only in vivo, but in in vitro neuronal networks as well, following some stereotypical patterns that reproduce the time course of development of the mammalian nervous system. This review provides an overview of in vitro models for the study of spontaneous network activity, discussing their ability to reproduce in vivo - like dynamics and the main findings obtained with each particular model. While explanted brain slices are able to reproduce the neuronal oscillations typically observed in anaesthetized animals, dissociated cultures allow the use of patient-derived neurons and limit the number of animals used for sample preparation.

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“…The specific effect of loss of Ehmt1 on inhibition is relevant because imbalanced E/I is associated with ASD in humans and rodent models (Del Pino et al, 2018;Fenton, 2015;Nelson and Valakh, 2015;Selten et al, 2018). In particular, a loss in the efficiency of inhibitory synaptic strength has been observed in many NDDs, including Rett syndrome and Fragile X syndrome (Braat and Kooy, 2015;Chao et al, 2010;Moskalyuk et al, 2019;Olmos-Serrano et al, 2010;Telias et al, 2016;Wood et al, 2009). The changes in excitatory and inhibitory inputs observed in KSS-gene-deficient neurons imply alterations in proteins directly or indirectly linked to synapse function.…”

Section: Kss-gene-deficient Network Share a Common Mode Of Failurementioning

confidence: 99%

Distinct Pathogenic Genes Causing Intellectual Disability and Autism Exhibit a Common Neuronal Network Hyperactivity Phenotype

et al. 2020

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Graphical Abstract Highlights d KSS gene deficiency leads to hyperactive neuronal network functioning d EHMT1-deficient neurons show altered excitatory-inhibitory balance d KSS gene deficiency leads to increased neuronal excitability d KSS target genes converge on neuronal excitability and synaptic function regulation In Brief Frega et al. show that mutations in functionally distinct genes leading to Kleefstra syndrome converge at the molecular, cellular, and neuronal network levels. KSS gene deficiency leads to hyperactive neuronal network communication and altered excitatoryinhibitory balance. Common biological pathways related to ion-channel expression and synaptic communication underlie this functional convergence.

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Single-cell and neuronal network alterations in an in vitro model of Fragile X syndrome

Abstract: The Fragile X mental retardation protein (FMRP) is involved in many cellular processes and it regulates synaptic and network development in neurons. Its absence is known to lead to intellectual disability, with a wide range of co-morbidities including

Cited by 4 publications

References 53 publications

Cortical neurons derived from human pluripotent stem cells lacking FMRP display altered spontaneous firing patterns

Cortical neurons derived from human pluripotent stem cells lacking FMRP display altered spontaneous firing patterns

Evaluation of in vitro neuronal networks for the study of spontaneous activity

Distinct Pathogenic Genes Causing Intellectual Disability and Autism Exhibit a Common Neuronal Network Hyperactivity Phenotype

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