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Relationship: 2410


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Increased Cholinergic Signaling leads to Neuronal network function, Decreased

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Organo-Phosphate Chemicals induced inhibition of AChE leading to impaired cognitive function adjacent Moderate Moderate 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 Do not cite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 KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
rat Rattus norvegicus High NCBI
mouse Mus musculus Moderate NCBI
Drosophila melanogaster Drosophila melanogaster Moderate NCBI
zebra fish Danio rerio Moderate NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Mixed High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
During brain development High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Cholinergic signaling refers to the activation of receptors bound with acetylcholine. Receptors for acetylcholine is either acetylcholine or cholinergic receptors, which further classify into muscarinic and nicotinic ( Nicotinic cholinergic signaling is began early in development and spreads throughout the central nervous system via acetylcholine (ACh) and activating a range of ligand-gated ion channels (John D et al., 2015). Nicotinic cholinergic signaling clearly plays important roles in both during development in shaping the neural networks that form and in the adult where it modulates network function in numerous ongoing ways (John D et al., 2015). Recent study by Wang Y et al, (2021) showed that cholinergic signaling controls excitation and inhibition balance of neuronal network in brain. In thalamus neuronal networks are the target of extensive cholinergic projections from the basal forebrain. Upon activation, these cholinergic signals play important role in regulation of neuronal excitability and firing patterns of neuronal networks (Beierlein M et al., 2014).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

The capacity of a neuron to interconnect is based on neural network formation that count on functional synapse establishment by cholinergic neuron (Anna Bal-Price et al., 2017; Colón-Ramos, 2009). Previous study reported that changes in the activity of cholinergic interneurons can play a vital role in motor control as well as social behavior (Martos et al., 2017). Thus modifications to the cholinergic system can lead to major dysfunction of neuronal network and the loss of cholinergic neuron from the forebrain can cause cognitive deficits associated with Parkinson’s and Alzheimer’s disease (Ahmed NY et al., 2019). Although the aberrant cholinergic signaling linked with several neurological disorder including schizophrenia but exact role is yet to elucidate (Ahmed NY et al., 2019). The ability of ACh to link the response of neuronal networks in brain makes cholinergic signaling a crucial mechanism underlying complex behaviors (Picciotto MR et al., 2012).

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

The cholinergic signaling system is deliberately located to exercise neuromodulatory effects on the excitatory and inhibitory balance. Thus endogenous cholinergic signaling regulate the excitatory and inhibitory balance via both nicotinic and muscarinic receptor (Lucas-Meunier E et al., 2009). The loss of cholinergic neurons has a profound effect on cholinergic signaling. Neurological diseases like Alzheimer’s connecting abnormal or loss of cholinergic signaling and excitatory and inhibitory imbalances. Activation of cholinergic receptors has a robust modulatory influence in the hippocampal network via activation of GABAergic interneurons (Jones and Yakel 1997). Activation of neuronal nicotinic ACh receptors excites interneurones which can inhibit large numbers of hippocampal excitatory and inhibitory neurons, thus neuronal nicotinic ACh receptors could participate in the cholinergic regulation of hippocampal neuronal activity (Jones S et al., 1997). Cholinergic signaling, during development is essential for physiological processes essential for the formation of the PNS and CNS including synaptogenesis (Dwyer, J. B et al, 2009; Rima, M et al., 2020). Neuronal network formation and function are established via the process of synaptogenesis. Cholinergic transmission can facilitate disparate actions through integration of postsynaptic signals (Calabresi et al., 2000). The developmental period of synaptogenesis is critical for the formation of the basic circuitry of the nervous system, although neurons are able to form new synapses throughout life (Rodier, 1995). Alterations in synaptic connectivity lead to refinement of neuronal networks during development (Cline and Haas, 2008).

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

The exact mechanism by which increase in cholinergic signaling lead to decrease in neuronal network function has not been fully elucidated.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

The main proof of evidence comes from in vivo studies in rodents. However, Rima, M et al., (2020) carried out a thorough spatiotemporal analysis of the cholinergic system in embryonic and larval zebrafish., cholinergic neurons in vertebrates found in the brain and spinal cord including the basal forebrain, brainstem and the habenula (Ahmed NY et al., 2019; Rima M et al., 2020). In rat spinal cord cholinergic propriospinal innervation analysis was done by Sherriff FE and Henderson Z. A (1994). Study by Eadaim et al. (2020) illustrated that in vivo reduction of cholinergic signaling induced synaptic homeostasis in Drosophila neurons


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

Ahmed NY, Knowles R, Dehorter N. New Insights into Cholinergic Neuron Diversity. Front Mol Neurosci. 2019 Aug 27; 12:204. doi: 10.3389/fnmol.2019.00204. PMID: 31551706; PMCID: PMC6736589.

Anna Bal-Price, Pamela J. Lein, Kimberly P. Keil, Sunjay Sethi, Timothy Shafer, Marta Barenys, Ellen Fritsche, Magdalini Sachana, M.E. (Bette) Meek. Developing and applying the adverse outcome pathway concept for understanding and predicting neurotoxicity, NeuroToxicology, Volume 59, 2017, Pages 240-255, ISSN 0161-813X,

Beierlein M. Synaptic mechanisms underlying cholinergic control of thalamic reticular nucleus neurons. J Physiol. 2014 Oct 1; 592 (19):4137-45. doi: 10.1113/jphysiol.2014.277376. Epub 2014 Jun 27. PMID: 24973413; PMCID: PMC4215766.

Calabresi, P., Centonze, D., Gubellini, P., Pisani, A., and Bernardi, G. (2000). Acetylcholine-mediated modulation of striatal function. Trends Neurosci. 23, 120–126. doi: 10.1016/s0166-2236(99)01501-5.

Cline H, Haas K. (2008). The regulation of dendritic arbor development and plasticity by glutamatergic synaptic input: A review of the synaptotrophic hypothesis. J Physiol 586: 1509-1517.

Colón-Ramos DA. (2009). Synapse formation in developing neural circuits. Curr Top Dev Biol. 87: 53-79.

Dwyer, J. B., McQuown, S. C. & Leslie, F. M. The dynamic effects of nicotine on the developing brain. Pharmacol. Ther. 122, 125–139 (2009).

Eadaim A, Hahm ET, Justice ED, Tsunoda S. Cholinergic Synaptic Homeostasis Is Tuned by an NFAT-Mediated α7 nAChR-Kv4/Shal Coupled Regulatory System. Cell Rep. 2020 Sep 8; 32(10):108119. doi: 10.1016/j.celrep.2020.108119. PMID: 32905767; PMCID: PMC7521586.

John D, Berg DK. Long-lasting changes in neural networks to compensate for altered nicotinic input. Biochem Pharmacol. 2015 Oct 15; 97 (4):418-424. doi: 10.1016/j.bcp.2015.07.020. Epub 2015 Jul 20.

Jones S, Yakel JL. 1997. Functional nicotinic ACh receptors on interneurones in the rat hippocampus. J Physiol. 504:603—610.

Lucas-Meunier E, Monier C, Amar M, Baux G, Fregnac Y, Fossier P. Involvement of nicotinic and muscarinic receptors in the endogenous cholinergic modulation of the balance between excitation and inhibition in the young rat visual cortex. Cereb Cortex. 2009 doi:10.1093/cercor/bhn258.

Martos, Y. V., Braz, B. Y., Beccaria, J. P., Murer, M. G., and Belforte, J. E. (2017). Compulsive social behavior emerges after selective ablation of striatal cholinergic interneurons. J. Neurosci. 37, 2849–2858. doi: 10.1523/jneurosci.3460-16.2017

Picciotto MR, Higley MJ, Mineur YS. Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior. Neuron. 2012; 76(1):116-129. doi:10.1016/j.neuron.2012.08.036.

Rima, M., Lattouf, Y., Abi Younes, M. et al. Dynamic regulation of the cholinergic system in the spinal central nervous system. Sci Rep 10, 15338 (2020).

Rodier PM. (1995). Developing brain as a target of toxicity. Environ. Health Perspect. 103: 73-76.

Sherriff FE, Henderson Z. A cholinergic propriospinal innervation of the rat spinal cord. Brain Res. 1994 Jan 14; 634(1):150-4. doi: 10.1016/0006-8993(94)90268-2. PMID: 8156385.

Wang Y, Tan B, Wang Y, Chen Z. Cholinergic Signaling, Neural Excitability, and Epilepsy. Molecules. 2021; 26(8):2258. Published 2021 Apr 13. doi:10.3390/molecules26082258