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Increased Cholinergic Signaling leads to Neuronal network function, Decreased
Key Event Relationship Overview
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||SAROJ AMAR (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
|During brain development||High|
Key Event Relationship Description
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 (aopwiki.org/events/39). 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 Supporting this KER
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).
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
The exact mechanism by which increase in cholinergic signaling lead to decrease in neuronal network function has not been fully elucidated.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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
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, https://doi.org/10.1016/j.neuro.2016.05.010.
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). https://doi.org/10.1038/s41598-020-72524-3.
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