Altered network and rescue of human neurons derived from individuals with early-onset genetic epilepsy

Negraes, Priscilla D.; Trujillo, Cleber A.; Yu, Nam-Kyung; Wu, Weiqiang; Yao, Heng‐Chen; Liang, Nicholas; Lautz, Jonathan D.; Kwok, Ellius; McClatchy, Daniel B.; Diedrich, Jolene K.; Bartolome, Salvador Martinez de; Truong, Justin; Szeto, Ryan A.; Tran, Timothy H.; Herai, Roberto Hirochi; Smith, Stephen; Haddad, Gabriel G.; Muotri, Alysson R.

doi:10.1038/s41380-021-01104-2

Cited by 44 publications

(45 citation statements)

References 85 publications

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“…In further support of our findings, Negraes et al have found similar synaptic defects in iPSCs-derived cortical neurons from CDD patients (Negraes et al, 2021). In apparent contrast from our observation, they found an increased mGlurR5-PanHomer association in CDD human organoids (Negraes et al, 2021) while we revealed that mGluR5-Homer1bc binding, an association crucial for this receptor function, is decreased in CDKL5 mutant mice. The most parsimonious explanation of this discrepancy arises primarily either the different technical approaches or the experimental models used (i.e., mice brain vs CDD human organoids).…”

Section: Discussionsupporting

confidence: 92%

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mGluR5 PAMs rescue cortical and behavioural defects in a mouse model of CDKL5 deficiency disorder

Gurgone

Pizzo

Raspanti

et al. 2022

Preprint

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Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a devastating rare neurodevelopmental disease without a cure, caused by mutations of the serine/threonine kinase CDKL5 highly expressed in the forebrain. CDD is characterized by early-onset seizures, severe intellectual disabilities, autistic-like traits, sensorimotor and cortical visual impairments (CVI). The lack of an effective therapeutic strategy for CDD urgently demands the identification of novel druggable targets potentially relevant for CDD pathophysiology. To this aim, we studied metabotropic glutamate receptors 5 (mGluR5) for their important role in critical mechanisms involved in CDD, i.e.: synaptogenesis, dendritic spines formation/maturation and synaptic plasticity, and because mGluR5 function depends on the postsynaptic protein Homer1bc that is downregulated in the cerebral cortex of CDKL5-/y mice. In this study, we reveal that CDKL5 loss tampers with (i) the strength of Homer1bc-mGluR5 binding, (ii) the synaptic localization of mGluR5 and (iii) the mGluR5-mediated enhancement of NMDA-induced neuronal responses. Importantly, we showed that the stimulation of mGluR5 activity by administering in mice positive-allosteric-modulators, i.e.: 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) or RO6807794, corrected the synaptic, functional and behavioural defects shown by CDKL5-/y mice. Notably, the cerebral cortex of 2 CDD patients show similar changes in the synaptic organization to mutant CDKL5 mice, including a reduced mGluR5 expression, suggesting that mGluR5 represent a promising therapeutic target for CDD patients.

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Section: Discussionsupporting

confidence: 92%

“…To properly function, mGluR5 requires binding with Homer1bc (Aloisi et al, 2017), a scaffolding protein that is severely downregulated in the cerebral cortex of both CDKL5 −/y mice and CDD patients (Pizzo et al, 2019, 2016; fig. 6A) as well as in iPSCs-derived neurons from CDD patients (Negraes et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

mGluR5 PAMs rescue cortical and behavioural defects in a mouse model of CDKL5 deficiency disorder

Gurgone

Pizzo

Raspanti

et al. 2022

Preprint

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“…Cortical organoids have been used in high-throughput screening platforms using calcium imaging as read-out to test the effect of novel therapeutic compounds ( Negraes et al, 2021 ). The use of both low- and high-throughput electrophysiological techniques, such as patch-clamping and MEAs respectively, will help to better characterize the effectiveness of novel treatments in normalizing pathological neuronal and network activity.…”

Section: Discussionmentioning

confidence: 99%

“…Over the course of 10 months, cortical organoids exhibited a steady increase in firing rate, burst frequency, synchronicity and population spiking. This cortical organoid model was used to investigate changes in network activity in organoids derived from patients with CDLK5-deficiency disorder (CDD), a neurodevelopmental disorder associated with early-onset epilepsy ( Olson et al, 2019 ; Negraes et al, 2021 ). MEA recordings showed consistent increases in electrical activity in CDD-derived cortical organoids compared to controls, as well as a significant increase in mean firing rate and network synchronicity early in development ( Negraes et al, 2021 ).…”

Section: Cellular and Network Electrophysiological Properties Of Huma...mentioning

confidence: 99%

Electrophysiological Properties of Human Cortical Organoids: Current State of the Art and Future Directions

Zourray

Kurian

Barral

et al. 2022

Front. Mol. Neurosci.

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Human cortical development is an intricate process resulting in the generation of many interacting cell types and long-range connections to and from other brain regions. Human stem cell-derived cortical organoids are now becoming widely used to model human cortical development both in physiological and pathological conditions, as they offer the advantage of recapitulating human-specific aspects of corticogenesis that were previously inaccessible. Understanding the electrophysiological properties and functional maturation of neurons derived from human cortical organoids is key to ensure their physiological and pathological relevance. Here we review existing data on the electrophysiological properties of neurons in human cortical organoids, as well as recent advances in the complexity of cortical organoid modeling that have led to improvements in functional maturation at single neuron and neuronal network levels. Eventually, a more comprehensive and standardized electrophysiological characterization of these models will allow to better understand human neurophysiology, model diseases and test novel treatments.

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“…This is of particular interest for diseases that involve abnormal excitability such as epilepsy. This was exemplified in a study by Negraes and collaborators, who conducted a phenotypic and target agnostic assay monitoring spontaneous calcium activity in 3D neuronal cultures as a read-out for network electric activity, which is abnormally increased in CDK5L-deficient neurons [ 125 ]. CDKL5 gene encodes for a serine/threonine kinase highly expressed in the central nervous system.…”

Section: Paving the Way: Rare Genetic Diseasesmentioning

confidence: 99%

Contribution of Human Pluripotent Stem Cell-Based Models to Drug Discovery for Neurological Disorders

Benchoua

Lasbareilles

Tournois

2021

Cells

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One of the major obstacles to the identification of therapeutic interventions for central nervous system disorders has been the difficulty in studying the step-by-step progression of diseases in neuronal networks that are amenable to drug screening. Recent advances in the field of human pluripotent stem cell (PSC) biology offers the capability to create patient-specific human neurons with defined clinical profiles using reprogramming technology, which provides unprecedented opportunities for both the investigation of pathogenic mechanisms of brain disorders and the discovery of novel therapeutic strategies via drug screening. Many examples not only of the creation of human pluripotent stem cells as models of monogenic neurological disorders, but also of more challenging cases of complex multifactorial disorders now exist. Here, we review the state-of-the art brain cell types obtainable from PSCs and amenable to compound-screening formats. We then provide examples illustrating how these models contribute to the definition of new molecular or functional targets for drug discovery and to the design of novel pharmacological approaches for rare genetic disorders, as well as frequent neurodegenerative diseases and psychiatric disorders.

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Altered network and rescue of human neurons derived from individuals with early-onset genetic epilepsy

Cited by 44 publications

References 85 publications

mGluR5 PAMs rescue cortical and behavioural defects in a mouse model of CDKL5 deficiency disorder

mGluR5 PAMs rescue cortical and behavioural defects in a mouse model of CDKL5 deficiency disorder

Electrophysiological Properties of Human Cortical Organoids: Current State of the Art and Future Directions

Contribution of Human Pluripotent Stem Cell-Based Models to Drug Discovery for Neurological Disorders

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