Developmental GABA polarity switch and neuronal plasticity in Bioengineered Neuronal Organoids

Zafeiriou, Maria-Patapia; Bao, Guobin; Hudson, James E.; Halder, Rashi; Blenkle, Alica; Schreiber, Marie-Kristin; Fischer, André; Schild, Detlev; Zimmermann, Wolfram‐Hubertus

doi:10.1038/s41467-020-17521-w

Cited by 95 publications

(91 citation statements)

References 41 publications

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“…Therefore, human-derived organoids are in the spotlight as next-generation in vitro model 59 , 60 . However, functional analysis of human-derived brain or spinal cord organoids has still been mostly performed on a 2D MEA 29 , 30 , which possesses an inherent limitation for investigating the functional connectivity inside organoids with 3D structures.…”

Section: Resultsmentioning

confidence: 99%

3D high-density microelectrode array with optical stimulation and drug delivery for investigating neural circuit dynamics

et al. 2021

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Investigation of neural circuit dynamics is crucial for deciphering the functional connections among regions of the brain and understanding the mechanism of brain dysfunction. Despite the advancements of neural circuit models in vitro, technologies for both precisely monitoring and modulating neural activities within three-dimensional (3D) neural circuit models have yet to be developed. Specifically, no existing 3D microelectrode arrays (MEAs) have integrated capabilities to stimulate surrounding neurons and to monitor the temporal evolution of the formation of a neural network in real time. Herein, we present a 3D high-density multifunctional MEA with optical stimulation and drug delivery for investigating neural circuit dynamics within engineered 3D neural tissues. We demonstrate precise measurements of synaptic latencies in 3D neural networks. We expect our 3D multifunctional MEA to open up opportunities for studies of neural circuits through precise, in vitro investigations of neural circuit dynamics with 3D brain models.

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Section: Resultsmentioning

confidence: 99%

3D high-density microelectrode array with optical stimulation and drug delivery for investigating neural circuit dynamics

et al. 2021

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“…Because GABA A receptor-mediated effects switch from depolarization to hyperpolarization during neonatal brain development (Obrietan and van den Pol, 1995;van den Pol et al, 1998;Saint-Amant and Drapeau, 2000;Ben-Ari, 2002;Takayama and Inoue, 2004), we assume that these differential GABA actions are also present during maturation of striatal MSNs. In human iPSC-derived bioengineered neuronal organoids, the developmental GABA polarity switch was observed after day 40, indicating progressive neuronal network maturation (Zafeiriou et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Reduced Expression of GABAA Receptor Alpha2 Subunit Is Associated With Disinhibition of DYT-THAP1 Dystonia Patient-Derived Striatal Medium Spiny Neurons

Staege

Kutschenko

Baumann

et al. 2021

Front. Cell Dev. Biol.

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DYT-THAP1 dystonia (formerly DYT6) is an adolescent-onset dystonia characterized by involuntary muscle contractions usually involving the upper body. It is caused by mutations in the gene THAP1 encoding for the transcription factor Thanatos-associated protein (THAP) domain containing apoptosis-associated protein 1 and inherited in an autosomal-dominant manner with reduced penetrance. Alterations in the development of striatal neuronal projections and synaptic function are known from transgenic mice models. To investigate pathogenetic mechanisms, human induced pluripotent stem cell (iPSC)-derived medium spiny neurons (MSNs) from two patients and one family member with reduced penetrance carrying a mutation in the gene THAP1 (c.474delA and c.38G > A) were functionally characterized in comparison to healthy controls. Calcium imaging and quantitative PCR analysis revealed significantly lower Ca2+ amplitudes upon GABA applications and a marked downregulation of the gene encoding the GABAA receptor alpha2 subunit in THAP1 MSNs indicating a decreased GABAergic transmission. Whole-cell patch-clamp recordings showed a significantly lower frequency of miniature postsynaptic currents (mPSCs), whereas the frequency of spontaneous action potentials (APs) was elevated in THAP1 MSNs suggesting that decreased synaptic activity might have resulted in enhanced generation of APs. Our molecular and functional data indicate that a reduced expression of GABAA receptor alpha2 subunit could eventually lead to limited GABAergic synaptic transmission, neuronal disinhibition, and hyperexcitability of THAP1 MSNs. These data give pathophysiological insight and may contribute to the development of novel treatment strategies for DYT-THAP1 dystonia.

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“…However, recent advances in three-dimensional culture techniques and differentiation methods have allowed the generation of cerebral organoids from single iPSC lines. These organoids comprise diverse neuronal and glial cell types, which show limited self-organisation and exhibit spontaneous, synchronised neural activity ( Izsak et al, 2019 ; Trujillo et al, 2019 ; Zafeiriou et al, 2020 ), meaning that they could eventually model both network-level and cell-autonomous defects in epilepsy. Caenorhabditis elegans The roundworm C. elegans has a relatively simple but exceptionally well-characterised nervous system consisting of exactly 302 neurons (in the adult hermaphrodite) with a highly stereotyped organisation ( Chatterjee and Sinha, 2007 ).…”

Section: Introduction: What Is Epilepsy?mentioning

confidence: 99%

Modelling epilepsy in the mouse: challenges and solutions

Marshall

Gonzalez-Sulser

Abbott

2021

Disease Models &Amp; Mechanisms

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In most mouse models of disease, the outward manifestation of a disorder can be measured easily, can be assessed with a trivial test such as hind limb clasping, or can even be observed simply by comparing the gross morphological characteristics of mutant and wild-type littermates. But what if we are trying to model a disorder with a phenotype that appears only sporadically and briefly, like epileptic seizures? The purpose of this Review is to highlight the challenges of modelling epilepsy, in which the most obvious manifestation of the disorder, seizures, occurs only intermittently, possibly very rarely and often at times when the mice are not under direct observation. Over time, researchers have developed a number of ways in which to overcome these challenges, each with their own advantages and disadvantages. In this Review, we describe the genetics of epilepsy and the ways in which genetically altered mouse models have been used. We also discuss the use of induced models in which seizures are brought about by artificial stimulation to the brain of wild-type animals, and conclude with the ways these different approaches could be used to develop a wider range of anti-seizure medications that could benefit larger patient populations.

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Developmental GABA polarity switch and neuronal plasticity in Bioengineered Neuronal Organoids

Cited by 95 publications

References 41 publications

3D high-density microelectrode array with optical stimulation and drug delivery for investigating neural circuit dynamics

3D high-density microelectrode array with optical stimulation and drug delivery for investigating neural circuit dynamics

Reduced Expression of GABAA Receptor Alpha2 Subunit Is Associated With Disinhibition of DYT-THAP1 Dystonia Patient-Derived Striatal Medium Spiny Neurons

Modelling epilepsy in the mouse: challenges and solutions

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