In Vitro Techniques for Assessing Neurotoxicity Using Human iPSC-Derived Neuronal Models
The central nervous system consists of a multitude of different neurons and supporting cells that form networks for transmitting neuronal signals. Proper function of the nervous system depends critically on a wide range of highly regulated processes inclu
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on: Neuronal Network Communication and Neurotoxicity The (central) nervous system consists of sophisticated neuronal networks that control body function, either via direct control or indirect via input in glands. The main function of neurons that make up the nervous system is to send and receive signals, a process called neurotransmission. To that aim, neurons have a typical structure with dendrites bringing the signal toward the cell body and an axon transmitting the signal away from the cell Michael Aschner and Lucio Costa (eds.), Cell Culture Techniques, Neuromethods, vol. 145, https://doi.org/10.1007/978-1-4939-9228-7_2, © Springer Science+Business Media, LLC, part of Springer Nature 2019
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body. As soon as dendrites receive an excitatory chemical signal, the neuron becomes activated and translates this chemical input signal in an electrical signal, an action potential (AP). Via opening of voltage-gated sodium and potassium channels, the AP induces a change in membrane potential that travels via the cell body along the axon to the synapse at the axon terminal. There, the electrical signal (AP) is converted into a chemical signal that will be transferred to (an)other neuron(s). The first step in conversion from the electrical to the chemical signal involves opening of voltage-gated calcium channels (VGCC), resulting in a strong influx of calcium ions (Ca2+). The resulting changes in the intracellular Ca2+ concentration ([Ca2+]i) are involved in a variety of cellular processes such as excitability, plasticity, motility, and viability [1, 2]. [Ca2+]i is crucial for the regulation of neurotransmission as Ca2+ influx through VGCCs triggers the release of neurotransmitters from the presynaptic cell into the synaptic cleft [2–4]. Neurotransmitters are chemical signaling molecules that are stored in vesicles in the presynaptic neuron. There are different types of excitatory and inhibitory neurotransmitters, such as acetylcholine, dopamine, serotonin, glutamate, and gamma-aminobutyric acid (GABA). After release into the synaptic cleft by fusion of the vesicles with the presynaptic plasma membrane, neurotransmitters can bind to receptors on the postsynaptic membrane. In the receiving cell, the signal can then be converted in a new AP, or it can activate intracellular signaling pathways. The chemical signal is terminated by degradation or reuptake of the neurotransmitters from the synaptic cleft (for review see [2, 4]). Communication in neuronal networks thus critically depends on the structure of neurons, intact neuronal membranes, and regulation of cellular and molecular mechanisms underlying neurotransmission. Additionally, proper neuronal communication also depends on supporting cells such as oligodendrocytes, astrocytes, and microglia. The multicellular nature of the networks can be confirmed with techniques as immunocytochemistry, whereas proper intracellular signaling can be studied with imaging techniques focusing on intracellular calcium levels and the membrane potential. Finally, the
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