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Event: 2005
Key Event Title
Altered neurotransmission in development
Short name
Biological Context
Level of Biological Organization |
---|
Cellular |
Cell term
Cell term |
---|
neuron |
Organ term
Organ term |
---|
brain |
Key Event Components
Process | Object | Action |
---|---|---|
synapse | disrupted |
Key Event Overview
AOPs Including This Key Event
AOP Name | Role of event in AOP | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|
Binding to voltage gate sodium channels during development leads to cognitive impairment | KeyEvent | Iris Mangas (send email) | Under development: Not open for comment. Do not cite | Under Review |
Taxonomic Applicability
Life Stages
Life stage | Evidence |
---|---|
During brain development | High |
Sex Applicability
Term | Evidence |
---|---|
Male | High |
Female | High |
Key Event Description
The arrival of the nerve impulse at the presynaptic terminal of the nerve’s axon stimulates the release of neurotransmitter into the synaptic cleft. The neuron is a secretory cell and the secretory product, the neurotransmitter, is released to span the distance between neurons, the chemical synapse.
Neurotransmitters synthesized by the neuron are stored in the presynaptic element, inside the pre- synaptic vesicles. Release of neurotransmitter can be described by probabilistic principles. The probability of neurotransmitter release is very low under normal “resting” conditions but increases dramatically upon depolarization of the axonal nerve terminal by an action potential (AP). AP depolarization of the presynaptic site of the axon terminal causes voltage gated Ca2+ channels to open. Calcium ions entering the cell initiate a signalling cascade that causes small membrane-bound vesicles, called pre-synaptic vesicles, containing neurotransmitter molecules to fuse with the presynaptic membrane. Neurotransmitters are then released, diffuse across the space between the presynaptic and postsynaptic neurons, the synaptic cleft, and bind to their appropriate receptors on the postsynaptic membrane. Signalling is then terminated by three different mechanisms: diffusion of the neurotransmitter out of the synaptic cleft, degradation of neurotransmitter by specific enzymes (e.g. acetylcholinesterase), or reuptake of the neurotransmitter by glia cells and the presynaptic neuron.
In principle different neurons excrete excitatory or inhibitory neurotransmitters, inducing in the postsynaptic membrane either a depolarisation or hyperpolarisation, respectively. In consequence these actions either trigger or impede the generation of a new postsynaptic depolarization. Neurons integrate the various excitatory and inhibitory signals they receive from the large number of synapses with their presynaptic network, resulting in a net signalling event in their postsynaptic targets.
Disruption of neurotransmission during development can result in permanent changes in nervous system function.
How It Is Measured or Detected
Neurotransmission can be measured by a wide variety of different approaches. The same technologies described in KE2 for AP generation can be used to measure neurotransmission by applying different protocols. These include patch clamp, intracellular and extracellular recordings, microelectrode array (MEA) recordings. KE 2005 can be measured using many methodologies that examine neural connectivity (i.e., neurotransmission), including the in vitro NNF assay. A standardized NNF test system to assess the potential impact of chemical exposure on neural network formation and function has been developed using rodent cortical neurons (Frank et al., 2017). Depending on the type of recording used, electrophysiological techniques capture presynaptic events such as the action potential arriving at the terminal that induces a release of neurotransmitter, or post-synaptic events, such as post-synaptic excitatory or inhibitory responses. These responses are induced by binding of neurotransmitter to postsynaptic membrane receptors. These electrical signals are the consequence of neurotransmitter diffusion from the pre- to the postsynaptic element, binding of neurotransmitter molecules to postsynaptic receptors and induction of the postsynaptic current.
Biochemical assessment of neurotransmission (i.e. in vivo microdialysis or in vitro measurement of neurotransmitters released into the media) are also common and well described in the literature.
For further details, see Khadria (2022) and Ogden (1994).
Patch Clamp
Intracellular recordings measure neurotransmission following stimulation of presynaptic neurons via excitatory and inhibitory currents by electrodes positioned inside the postsynaptic neuron. Similar currents can be assessed using patch clamp techniques.
In extracellular field potential recordings stimulating electrodes placed on the input presynaptic axonal field induce after a short synaptic delay a response in the postsynaptic cells reflecting neurotransmission.
In microelectrode arrays, neurotransmission is reflected by parameters including synchronized network activity, correlation of neuronal activity across multiple electrodes, and activity evoked by direct stimulation.
As described above for KE2, Action Potential Generation, optical approaches can also be used to measure neurotransmission, such as the use of pH sensitive dyes that are incorporated into the pre-synaptic vesicles, dyes that change fluorescent properties once released into the synaptic cleft due to a difference in pH between the vesicle compartment and the synaptic cleft.
Domain of Applicability
The process of neurotransmission is generally similar in structure/function across most taxa with nervous systems (Libenskind et al. 2017; Roschchina 2010). This includes studies using both in vitro and in vivo methods. In vertebrates, synaptic transmission usually travels in one direction. The process of synaptic transmission has been well-studied and is described in many standard neurophysiology textbooks.
Components of the synapse include (a) a presynaptic module, in which calcium signals are transduced into chemical secretions (known as excitation–secretion coupling); (b) a postsynaptic module (postsynaptic density), which comprises the proteins that support the specialized postsynaptic membrane and the signalling that goes on there; and (c) a module that determines the specific wiring diagram of neurons during development (axonogenesis). Connections between neurons can be, in this way, mapped by acquiring and analyzing electron microscopic wiring diagrams. For the module “c”, during development, and after injury, axons must grow and find their correct synaptic targets. Electrical activity in neurons and neural networks can stabilize structural connections at the synapse, while loss of activity leads to elimination of synapses. The proteins responsible for this targeting include secreted and membrane-bound signals and receptors that have not been as well studied in an evolutionary framework as for the other modules.
Despite its apparent specialization for neuronal signalling, the excitation–secretion system in neurons comprises many ancient gene families. However, like the transduction module, these gene families are often used differently in the various animal lineages. The proteins involved in docking and in recycling are, for the most part, conserved across eukaryotes (Liebenskind et al. 2017).
Several neurotransmitters have been found not only in animals, but also in plants and microorganisms. Thus, the presence of neurotransmitter compounds has been shown in organisms lacking a nervous system and even in unicellular organisms. Today, we have evidence that neurotransmitters, which participate in synaptic neurotransmission, are multifunctional substances participating in developmental processes of microorganisms, plants, and animals (Roschchina 2010). In the brain, many neurotransmitters also act as trophic factors in early brain development.
The neurotransmission wiring code, including excitation–secretion coupling, postsynaptic density and axonogenesis is present across multiple taxa and represents a fundamental brain developmental process.
References
Khadria A,2022. “Tools to Measure Membrane Potential of Neurons”. Biomedical Journal ,45 (5),749–62. https://doi.org/10.1016/j.bj.2022.05.007.
Liebeskind BJ, Hofmann HA, Hillis DM and Zakon HH ,2017. Evolution of animal neural systems, Annual review of ecology, evolution, and systematics, 48, 377-398, Annual Reviews, https://doi.org/10.1146/annurev-ecolsys-110316-023048.
Ogden D(ed.) ,1994. Microelectrode techniques. The Plymouth Workshop Handbook. Cambridge, The Company of Biologists Ltd, 448pp.http://plymsea.ac.uk/id/eprint/7954/
Roshchina VV,2010. Evolutionary considerations of neurotransmitters in microbial, plant, and animal cells. In: Lyte, M., Freestone, P. (eds) Microbial Endocrinology, pp. 17-52. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-5576-0_2