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Event: 2151

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Disruption, neurotransmitter release

Short name

The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help

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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help

Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Cell term
neuron

Organ term

Organ term
brain

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
signaling	neurotransmitter	decreased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
MEK-ERK1/2 activation leading to deficits in learning and cognition	KeyEvent	Evgeniia Kazymova (send email)	Under development: Not open for comment. Do not cite
elavl3, sox10, mbp induced neuronal effects	KeyEvent	Brendan Ferreri-Hanberry (send email)	Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
Rattus norvegicus	Rattus norvegicus	Moderate	NCBI
Homo sapiens	Homo sapiens	Moderate	NCBI
Mus musculus	Mus musculus	Moderate	NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Life stage	Evidence
Birth to < 1 month	Moderate
Adult	Moderate

Sex Applicability

An indication of the the relevant sex for this KE. More help

Term	Evidence
Mixed	Moderate

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Any of various neurotransmitters or indicators of neurotransmission.

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Weighed brain tissues were homogenized in a Potter-Elvehjem type A homogenizer with a teflon pestle using cold acidified n-butanol. The biogenic amines were extracted and estimated according to the procedure of Sadavongvivad (1970). The recovery experiments were done simultaneously. Recoveries for different standards were 92 + 3% for dopamine (DA), 80+ 5% for norepinephrine (NE) and 90 + 5% for 5-hydroxytryptamine (5-HT). Fluorescence was measured in a Aminco SPF-500 spectrofluorometer (Chandra et al., 1981).

BDNF quantitative real-time PCR. Hippocampal neuronal cultures were exposed to normal bath solution or 1.0 or 2.0μM Pb2+ for 5 days, and subsequently RNA was harvested according to manufacturer’s instructions (RNeasy; Qiagen), quantified by reading the absorbance at 260 nm, and converted to complementary DNA (cDNA) using 1 μg RNA according to manufacturer’s instructions (High Capacity Reverse Transcription Kit 4368814; Applied Biosystems). Quantitative real-time PCR (q-rtPCR) was performed in triplicate using TaqMan Gene Expression Assays (Applied Biosystems) with 50 ng cDNA using the following probes: Actin (Rat, Rn00667869_m1; Applied Biosystems) and BDNF exon I, exon II, exon IV, and exon IX (Applied Biosystems). Data were analyzed as previously described (Livak and Schmittgen, 2001), and results were expressed as fold change in gene expression relative to^{control (Stansfield and others 2012).}

BDNF release via ELISA. Sandwich ELISAs were performed on DIV12 cell culture media using the BDNF Emax ImmunoAssay System kit (Promega, Madison, WI) according to the manufacturer’s instructions. BDNF content was interpolated from standard curve runs for each plate (linear range of 7.8–500 pg/ml). BDNF protein content was divided by total protein for each sample to determine the number of picograms of peptide per microgram of total protein (Stansfield and others 2012).

In vivo microdialysis is a well-established method for monitoring the extracellular levels of neurotransmitters in the CNS. This technique has been used extensively in neuroscience for almost 30 years (Westerink 1995; Ungerstedt 1991; Robinson 1991; Benveniste 1989; Benveniste and Huttemeier 1990; Di Chiara 1990). Microdialysis allows online estimates of neurotransmitters in living animals and is a suitable method for monitoring the extracellular levels of neurotransmitters during local administration of pharmacological agents (Hammarlund-Udenaes 2000). Older alternative in vivo methods for the study of neurotransmitter release are the push–pull technique used in the brain, (Singewald and Philippu 1998) spinal cord, (Zachariou and Goldstein 1997) and intrathecal space (Yaksh and Tyce 1980).

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

References

List of the literature that was cited for this KE description. More help

Benveniste H, Huttemeier PC. Microdialysis: theory and application. Progr Neurobiol. 1990;35:195.

Benveniste H. Brain microdialysis. J Neurochem. 1989;52:1667.

Chandra, Satya V., et al. "Behavioral and neurochemical changes in rats simultaneously exposed to manganese and lead." Archives of Toxicology 49 (1981): 49-56.

Di Chiara G. In vivo brain dialysis of neurotransmitters. Trends Pharmacol Sci. 1990;11:116.

Hammarlund-Udenaes M. The use of microdialysis in CNS drug delivery studies: pharmacokinetic perspectives and results with analgesics and antiepileptics. Adv Drug Deliv Rev. 2000;45:283.

Kirstie H. Stansfield and others, Dysregulation of BDNF-TrkB Signaling in Developing Hippocampal Neurons by Pb2+: Implications for an Environmental Basis of Neurodevelopmental Disorders, Toxicological Sciences, Volume 127, Issue 1, May 2012, Pages 277–295, https://doi.org/10.1093/toxsci/kfs090

Robinson TJ. Microdialysis in the Neurosciences. Vol. 7. Elsevier; Amsterdam: 1991. Techniques in the behavioral and neural sciences.

Singewald N, Philippu A. Release of neurotransmitters in the locus coeruleus. Progr Neurobiol. 1998;56:237.

Ungerstedt U. Microdialysis: principles and applications for studies in animals and man. J Intern Med. 1991;230:365

Westerink BH. Brain microdialysis and its application for the study of animal behaviour. Behav Brain Res. 1995;70:103.

Yaksh TL, Tyce GM. Resting and K+-evoked release of serotonin and norephinephrine in vivo from the rat and cat spinal cord. Brain Res. 1980;192:133.

Zachariou V, Goldstein BD. Dynorphin-(1-8)inhibits the release of substance P-like immunoreactivity in the spinal cord of rats following a noxious mechanical stimulus. Eur J Pharmacol. 1997;323:159.