Effect fingerprints of antipsychotic drugs on neural networks in vitro

Görtz, Philipp; Henning, Ulf; Theiss, Stephan; Lange-Asschenfeldt, Christian

doi:10.1007/s00702-019-02050-8

Cited by 3 publications

(6 citation statements)

References 35 publications

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“…Interestingly, the enhanced activity in MAM femalecultures was maintained 24 h post-administration of antipsychotics, with trends evident at 20 min. This is in line with past evidence of antipsychotic-induced increases in neuronal activity at 10 min post-administration [63], and follows the pharmacological timelines observed in clinical studies. Specifically, within 24 h of receiving HAL or atypical antipsychotic medication, individuals with SZ displayed significantly increased dopamine receptor blockade [66,67], as well as improved positive symptoms [68].…”

Section: Discussionsupporting

confidence: 91%

“…This finding may suggest a greater biological impact of antipsychotics in women than in men, and is in line with clinical findings showing that women respond better to antipsychotic treatment than men [4]. Further, this antipsychotic-induced increase in neuronal activity supports a previous MEA study in primary cortical neurons of wild-type (WT) mice, which reported that acute therapeutic doses of typical and atypical antipsychotics increased network-wide temporal synchronization [63]. Other MEA studies have found increased neuronal activity and synchronization with atypical antipsychotics only, and alterations in the opposite direction occurring with HAL exposure [64,65].…”

Section: Discussionsupporting

confidence: 89%

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Sex-Specific Cannabidiol- and Iloperidone-Induced Neuronal Activity Changes in an In Vitro MAM Model System of Schizophrenia

Thériault

St-Denis

Hewitt

et al. 2021

IJMS

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Cortical circuit dysfunction is thought to be an underlying mechanism of schizophrenia (SZ) pathophysiology with normalization of aberrant circuit activity proposed as a biomarker for antipsychotic efficacy. Cannabidiol (CBD) shows potential as an adjunctive antipsychotic therapy; however, potential sex effects in these drug interactions remain unknown. In the present study, we sought to elucidate sex effects of CBD coadministration with the atypical antipsychotic iloperidone (ILO) on the activity of primary cortical neuron cultures derived from the rat methylazoxymethanol acetate (MAM) model used for the study of SZ. Spontaneous network activity measurements were obtained using a multielectrode array at baseline and following administration of CBD or ILO alone, or combined. At baseline, MAM male neurons displayed increased bursting activity whereas MAM female neurons exhibited no difference in bursting activity compared to sex-matched controls. CBD administered alone showed a rapid but transient increase in neuronal activity in the MAM networks, an effect more pronounced in females. Furthermore, ILO had an additive effect on CBD-induced elevations in activity in the MAM male neurons. In the MAM female neurons, CBD or ILO administration resulted in time-dependent elevations in neuronal activity, but the short-term CBD-induced increases in activity were lost when CBD and ILO were combined. Our findings indicate that CBD induces rapid increases in cortical neuronal activity, with sex-specific drug interactions upon ILO coadministration. This suggests that sex should be a consideration when implementing adjunct therapy for treatment of SZ.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 89%

Sex-Specific Cannabidiol- and Iloperidone-Induced Neuronal Activity Changes in an In Vitro MAM Model System of Schizophrenia

Thériault

St-Denis

Hewitt

et al. 2021

IJMS

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“…Haloperidol is an antagonist for the inhibitory dopamine D2 receptor [86,87]; thus, we observe an increasing effect of this drug on the wMFR of neuronal units. Interestingly, all NN contained more units responding with a decreased electrical activity, which is in line with the results of previous in vitro studies that observed only inhibitory reactions after acute treatment [126][127][128][129][130]. Görtz and colleagues suggested that this effect may occur due to a direct blockage of ion channels [126], which explains the rising number of units responding with decreased activity at the highest haloperidol concentration.…”

Section: Discussionsupporting

confidence: 88%

Molecular and Functional Characterization of Different BrainSphere Models for Use in Neurotoxicity Testing on Microelectrode Arrays

Hartmann

Henschel

Bartmann

et al. 2023

Cells

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The currently accepted methods for neurotoxicity (NT) testing rely on animal studies. However, high costs and low testing throughput hinder their application for large numbers of chemicals. To overcome these limitations, in vitro methods are currently being developed based on human-induced pluripotent stem cells (hiPSC) that allow higher testing throughput at lower costs. We applied six different protocols to generate 3D BrainSphere models for acute NT evaluation. These include three different media for 2D neural induction and two media for subsequent 3D differentiation resulting in self-organized, organotypic neuron/astrocyte microtissues. All induction protocols yielded nearly 100% NESTIN-positive hiPSC-derived neural progenitor cells (hiNPCs), though with different gene expression profiles concerning regional patterning. Moreover, gene expression and immunocytochemistry analyses revealed that the choice of media determines neural differentiation patterns. On the functional level, BrainSpheres exhibited different levels of electrical activity on microelectrode arrays (MEA). Spike sorting allowed BrainSphere functional characterization with the mixed cultures consisting of GABAergic, glutamatergic, dopaminergic, serotonergic, and cholinergic neurons. A test method for acute NT testing, the human multi-neurotransmitter receptor (hMNR) assay, was proposed to apply such MEA-based spike sorting. These models are promising tools not only in toxicology but also for drug development and disease modeling.

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“…Haloperidol is an antagonist for the inhibitory dopamine D2 receptor [82,83], hence we observe an increasing effect of this drug on the wMFR of neuronal units. Interestingly, all NN contained more units responding with a decreased electrical activity, which is in line with previous in vitro studies that observed only inhibitory reactions after acute treatment [124–128]. Görtz and colleagues suggested, that this effect may occur due to a direct blockage of ion channels [124], which explains the rising number of units responding with decreased activity at the highest haloperidol concentration.…”

Section: Discussionsupporting

confidence: 88%

“…Interestingly, all NN contained more units responding with a decreased electrical activity, which is in line with previous in vitro studies that observed only inhibitory reactions after acute treatment [124–128]. Görtz and colleagues suggested, that this effect may occur due to a direct blockage of ion channels [124], which explains the rising number of units responding with decreased activity at the highest haloperidol concentration. Buspirone’s primary MoA is binding to presynaptic inhibitory 5-HT 1A receptors as an agonist [84], thus producing an inhibitory action as we observe for most units within the NN in vitro .…”

Section: Discussionsupporting

confidence: 88%

Molecular and functional characterization of different BrainSphere models for use in neurotoxicity testing on microelectrode arrays

Hartmann

Henschel

Bartmann

et al. 2023

Preprint

View full text Add to dashboard Cite

The currently accepted methods for neurotoxicity (NT) testing rely on animal studies. However, high costs and low testing throughput hinder their application for large numbers of chemicals. To overcome these limitations, in vitro methods are currently developed which are based on human induced pluripotent stem cells (hiPSC) that allow higher testing throughput at lower costs. We applied six different protocols to generate 3D BrainSphere models for acute NT evaluation. These include three different media for 2D neural induction and two media for subsequent 3D differen-tiation resulting in self-organized, organotypic neuron/astrocyte microtissues. All induction pro-tocols yielded nearly 100 % nestin-positive hiPSC-derived neural progenitor cells (hiNPCs) yet with different gene expression profiles concerning regional patterning. Moreover, gene expression and immunocytochemistry analyses revealed that the choice of media determines neural differentiation patterns. On the functional level, BrainSpheres exhibited different levels of electrical activ-ity on microelectrode arrays (MEA). Spike sorting allowed BrainSphere functional characterization with the mixed cultures consisting of GABAergic, glutamatergic, dopaminergic, serotonergic, and cholinergic neurons. A test method for acute NT testing, the human multi-neurotransmitter receptor (hMNR) assay, was proposed applying such MEA-based spike sorting. These models are not only promising tools in toxicology but also for drug development and disease modeling.

show abstract

Effect fingerprints of antipsychotic drugs on neural networks in vitro

Cited by 3 publications

References 35 publications

Sex-Specific Cannabidiol- and Iloperidone-Induced Neuronal Activity Changes in an In Vitro MAM Model System of Schizophrenia

Sex-Specific Cannabidiol- and Iloperidone-Induced Neuronal Activity Changes in an In Vitro MAM Model System of Schizophrenia

Molecular and Functional Characterization of Different BrainSphere Models for Use in Neurotoxicity Testing on Microelectrode Arrays

Molecular and functional characterization of different BrainSphere models for use in neurotoxicity testing on microelectrode arrays

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