Modelling hyperexcitability in human cerebral cortical organoids: Oxygen/glucose deprivation most effective stimulant

Saleem, Afifa; Santos, Alexandra C.; Aquilino, Mark S.; Sivitilli, Adam; Attisano, Liliana; Carlen, Peter L.

doi:10.1016/j.heliyon.2023.e14999

Cited by 6 publications

(6 citation statements)

References 63 publications

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“…In summary, cerebral organoids respond to OGD as a hyperexcitability (seizure-like) stimulus, producing significant power changes, which is consistent with previous work completed in the lab [25,27]. Bumetanide and CBD are both effective at preventing the OGD-induced changes, which highlights these compounds' efficacy in hypoxic-ischemicinduced hyperexcitability and their potential use for treating neonatal hypoxic-ischemicinduced seizures.…”

Section: Discussionsupporting

confidence: 87%

“…OGD induces a global increase in the power spectrum compared to baseline in cerebral organoids aged 4 and 7 months (Figure 2A,B). This effect is the same as that reported in our previous work [25,27]. The percent change from baseline to OGD was significant across most frequencies at 4 and 7 months (Figure 2C); however, it was more significant at 4 months (delta-beta, p < 0.001, gamma-vHFOs, p < 0.01), suggesting OGD is effective at inducing a hyperexcitable state in immature tissue.…”

Section: Ogd Is An Effective Hyperexcitable Agent At 4 and 7 Monthssupporting

confidence: 88%

“…The raw signals were processed for power spectrum analysis in MATLAB. Raw signals were not visualized in the present study; however, a detailed figure outlining the raw traces and corresponding power spectrum can be found in Figure 2 from [25]. LFP recordings were filtered using a lowpass filter at half the sample rate, and subsequently down sampled by a factor of 2, split over 3 cycles.…”

Section: Power Spectral Density Analysis and Statisticsmentioning

confidence: 99%

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Treating Hyperexcitability in Human Cerebral Organoids Resulting from Oxygen-Glucose Deprivation

Santos

Nader

Sabbagh

et al. 2023

Cells

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Human cerebral organoids resemble the 3D complexity of the human brain and have the potential to augment current drug development pipelines for neurological disease. Epilepsy is a complex neurological condition characterized by recurrent seizures. A third of people with epilepsy do not respond to currently available pharmaceutical drugs, and there is not one drug that treats all subtypes; thus, better models of epilepsy are needed for drug development. Cerebral organoids may be used to address this unmet need. In the present work, human cerebral organoids are used along with electrophysiological methods to explore oxygen-glucose deprivation as a hyperexcitability agent. This activity is investigated in its response to current antiseizure drugs. Furthermore, the mechanism of action of the drug candidates is probed with qPCR and immunofluorescence. The findings demonstrate OGD-induced hyperexcitable changes in the cerebral organoid tissue, which is treated with cannabidiol and bumetanide. There is evidence for NKCC1 and KCC2 gene expression, as well as other genes and proteins involved in the complex development of GABAergic signaling. This study supports the use of organoids as a platform for modelling cerebral cortical hyperexcitability that could be extended to modelling epilepsy and used for drug discovery.

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Section: Discussionsupporting

confidence: 87%

Section: Ogd Is An Effective Hyperexcitable Agent At 4 and 7 Monthssupporting

confidence: 88%

Section: Power Spectral Density Analysis and Statisticsmentioning

confidence: 99%

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Treating Hyperexcitability in Human Cerebral Organoids Resulting from Oxygen-Glucose Deprivation

Santos

Nader

Sabbagh

et al. 2023

Cells

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“…These cells displayed typical neuronal properties (Figure S4I-S4P), consistent with previous reports of hCOs. [62][63][64] TEM revealed numerous asymmetric and symmetric synapses in hCOs (Figure S4Q and S4R). A subset of presynaptic terminals contained dense core vesicles (Figure S4S).…”

Section: Tc Assembloids Form Functional Glutamatergic Tc and Ct Synapsesmentioning

confidence: 99%

Synaptic plasticity in human thalamocortical assembloids

Patton,

Thomas,

Bayazitov

et al. 2024

Preprint

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SUMMARYSynaptic plasticities, such as long-term potentiation (LTP) and depression (LTD), tune synaptic efficacy and are essential for learning and memory. Current studies of synaptic plasticity in humans are limited by a lack of adequate human models. Here, we modeled the thalamocortical system by fusing human induced pluripotent stem cell–derived thalamic and cortical organoids. Single-nucleus RNA-sequencing revealed that most cells in mature thalamic organoids were glutamatergic neurons. When fused to form thalamocortical assembloids, thalamic and cortical organoids formed reciprocal long-range axonal projections and reciprocal synapses detectable by light and electron microscopy, respectively. Using whole-cell patch-clamp electrophysiology and two-photon imaging, we characterized glutamatergic synaptic transmission. Thalamocortical and corticothalamic synapses displayed short-term plasticity analogous to that in animal models. LTP and LTD were reliably induced at both synapses; however, their mechanisms differed from those previously described in rodents. Thus, thalamocortical assembloids provide a model system for exploring synaptic plasticity in human circuits.HighlightsHuman thalamic organoids consist of mostly glutamatergic projection neurons.Thalamocortical assembloids form reciprocal glutamatergic synapses.Synapses are functional and undergo short-term plasticity resembling animal models.Long-term potentiation and depression reveal mechanisms distinct from rodents.eTOCHuman organoids are often used to model diseases with synaptic pathology; however, few studies have examined synaptic function via single-cell or single-synapse recordings. Patton et al. fused human thalamic and cortical organoids into assembloids to examine synaptic transmission and short- and long-term synaptic plasticity in human thalamocortical and corticothalamic circuits.GRAPHICAL ABSTRACT

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“…Of these methods, the human iPSC-derived brain organoid technique offers the distinct ability to self-assemble into three-dimensional Organoids 2023, 2 178 structures closely emulating disease-specific tissues, thus it has become a promising avenue for in vitro toxicity evaluations due to its heightened physiological relevance [8][9][10]. At present, brain organoid research encompasses an array of evaluations including scrutinizing morphological attributes and analyzing gene expression within the organoids themselves [11][12][13][14][15][16][17][18][19], in addition to performing assessments of electrical activities employing techniques like patch clamp [16,18,[20][21][22][23][24], calcium imaging [24][25][26], and planar micro electrode arrays (MEA) [26][27][28][29][30][31][32][33][34][35][36][37][38][39]. Our prior work has been dedicated to the establishment of the MEA measurement methodology for cerebral cortex organoids.…”

Section: Introductionmentioning

confidence: 99%

Contraindicated Drug Responses in Dravet Syndrome Brain Organoids Utilizing Micro Electrode Array Assessment Methods

Yokoi,

Nagafuku,

Ishibashi

et al. 2023

Organoids

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Ensuring drug safety for patients with specific neurological disorders is of paramount importance. For instance, certain antiepileptic drugs (AEDs) are contraindicated in Dravet Syndrome (DS), which is characterized by a deficiency in Na+ channel function. Constructing in vitro assessment methods capable of detecting contraindicated drug responses and medication effects on neurons derived from DS patients is highly anticipated for drug safety assessment and therapeutic innovation. This study used micro electrode array (MEA) measurements with low-frequency analysis on human iPSC-derived DS organoids to investigate AED responses. When exposed to the contraindicated drugs carbamazepine and phenytoin, the number of network oscillations increased in DS organoids while maintaining oscillation intensity. Furthermore, carbamazepine administration appeared to enhance activities beyond oscillations which is partially consistent with findings in the DS mouse model. Conversely, treatment with the therapeutic drug sodium valproate resulted in a similar decrease in activity both in healthy and DS organoids. The frequency characteristics of spontaneous firings and AEDs responsiveness in DS organoids demonstrated partial correlation with typical electroencephalography patterns observed in vivo. In conclusion, this study, employing MEA measurements with low-frequency analysis, revealed contraindicated drug responses and disease-specific functional characteristics in DS organoids, effective for DS patient safety assessment, precision medicine, and antiepileptic drug screening.

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Modelling hyperexcitability in human cerebral cortical organoids: Oxygen/glucose deprivation most effective stimulant

Cited by 6 publications

References 63 publications

Treating Hyperexcitability in Human Cerebral Organoids Resulting from Oxygen-Glucose Deprivation

Treating Hyperexcitability in Human Cerebral Organoids Resulting from Oxygen-Glucose Deprivation

Synaptic plasticity in human thalamocortical assembloids

Contraindicated Drug Responses in Dravet Syndrome Brain Organoids Utilizing Micro Electrode Array Assessment Methods

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