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N/A, Neurodegeneration leads to Decreased, Neuronal network function in adult brain
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Binding of agonists to ionotropic glutamate receptors in adult brain causes excitotoxicity that mediates neuronal cell death, contributing to learning and memory impairment.||adjacent||Low||Anna Price (send email)||Open for citation & comment||WPHA/WNT Endorsed|
|Inhibition of AChE and activation of CYP2E1 leading to sensory axonal peripheral neuropathy and mortality||adjacent||High||High||SAROJ AMAR (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
Key Event Relationship Description
Neurodegeneration (retraction of dendrites or axons) or neuronal cell death decreases the number of synaptic connections affecting the neuronal network function (Seeley et al., 2009). Based on neuropathology (Braak and Braak, 1991), neuroimaging (Buckner et al., 2005 and Greicius et al., 2004), and evidence from transgenic animal models (Palop et al., 2007a), it is suggested that neurodegeneration leads to neural network dysfunction (Buckner et al., 2005 and Palop et al., 2006). In human spongiform encephalopathies, which cause rapidly progressive dementia, direct evidence supports disease propagation along affected trans-synaptic connections (Scott et al., 1992). For all other neurodegenerative diseases, there are limited human experimental data supporting the “network degeneration hypothesis.” It is demonstrated as a class-wide phenomenon, with major mechanistic significance, predicting that the spatial patterning of disease relates to some structural, metabolic, or physiological aspect of neural network biology dysfunction. Confirming the network degeneration hypothesis has clinical impact, stimulating development of new network-based diagnostic and disease-monitoring assays.
Evidence Supporting this KER
Based on neuropathological findings and neuroimaging from patients suffering from neurodegeneration as well as from evidence derived by transgenic animal models of neurodegeneration, it has been suggested that neurodegeneration is related to neural network dysfunction (Palop et al., 2007b; Seeley et al., 2009). Neurodegeneration leads to impairment of retrograde axonal transport that prohibits the growth factor supply to long-range projection neurons, causing synapse loss, and post-synaptic dendrite retraction that leads to decreases of the neuronal network (Seeley et al., 2009).
Uncertainties and Inconsistencies
Administration of high dose DomA (4.4 mg/kg) to adult male Sprague-Dawley rats causes elevation of electrocorticogram (ECoG) beginning 30 min post injection, whereas at a lower dose (2.2 mg/kg) ECoG becomes elevated after 110 min (Binienda et al., 2011).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
It has been shown at the neuromascular junction of D. melanogaster that quisqualate-type glutamate receptors are blocked by DomA (1 mM) (Lee et al., 2009). However, in crayfish (Procambarus clarkia) the same concentration of DomA has no effect in spike activity (Bierbower and Cooper, 2013).
Bierbower SM, Cooper RL. The mechanistic action of carbon dioxide on a neural circuit and NMJ communication. J Exp Zool A Ecol Genet Physiol., 2013, 319: 340-54.
Binienda ZK, Beaudoin MA, Thorn BT, Ali SF. Analysis of electrical brain waves in neurotoxicology: γ-hydroxybutyrate. Curr Neuropharmacol., 2011, 9: 236-9.
Braak H., E. Braak, Neuropathological staging of Alzheimer-related changes, Acta Neuropathol., 1991, 82: 239–259.
Buckner R.L., A.Z. Snyder, B.J. Shannon, G. LaRossa, R. Sachs, A.F. Fotenos, Y.I. Sheline, W.E. Klunk, C.A. Mathis, J.C. Morris, M.A.Molecular, structural, and functional characterization of Alzheimer's disease: evidence for a relationship between default activity, amyloid, and memory. J. Neurosci., 2005, 25:7709–7717.
Greicius M.D., G. Srivastava, A.L. Reiss, V. Menon, Default-mode network activity distinguishes Alzheimer's disease from healthy aging: evidence from functional MRI. Proc. Natl. Acad. Sci. USA, 2004, 101: 4637–4642.
Hogberg HT, Sobanski T, Novellino A, Whelan M, Weiss DG, Bal-Price AK. Application of micro-electrode arrays (MEAs) as an emerging technology for developmental neurotoxicity: evaluation of domoic acid-induced effects in primary cultures of rat cortical neurons. Neurotoxicology, 2011, 32: 158-168.
Lee JY, Bhatt D, Bhatt D, Chung WY, Cooper RL. Furthering pharmacological and physiological assessment of the glutamatergic receptors at the Drosophila neuromuscular junction. Comp Biochem Physiol C Toxicol Pharmacol., 2009, 150(4): 546-57.
Mack CM, Lin BJ, Turner JD, Johnstone AF, Burgoon LD, Shafer TJ. Burst and principal components analyses of MEA data for 16 chemicals describe at least three effects classes. Neurotoxicology, 2014, 40: 75-85.
McConnell ER, McClain MA, Ross J, Lefew WR, Shafer TJ. Evaluation of multi-well microelectrode arrays for neurotoxicity screening using a chemical training set. Neurotoxicology, 2012, 33: 1048-1057.
Palop J.J., J. Chin, L. Mucke, A network dysfunction perspective on neurodegenerative diseases. Nature, 2006, 443: 768–773.
Palop JJ, Chin J, Roberson ED, Wang J, Thwin MT, Bien-Ly N, Yoo J, Ho KO, Yu GQ, Kreitzer A, et al. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease. Neuron, 2007a, 55: 697-711.
Palop J.J, J. Chin, E.D. Roberson, J. Wang, M.T. Thwin, N. Bien-Ly, J. Yoo, K.O. Ho, G.Q. Yu, A. Kreitzer, et al., Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease. Neuron, 2007b, 55: 697–711.
Qiu S, Jebelli AK, Ashe JH, Currás-Collazo MC. Domoic acid induces a long-lasting enhancement of CA1 field responses and impairs tetanus-induced long-term potentiation in rat hippocampal slices. Toxicol Sci., 2009, 111: 140-150.
Scott R.S., D. Davies, H. Fraser. Scrapie in the central nervous system: neuroanatomical spread of infection and Sinc control of pathogenesis. J. Gen. Virol., 1992, 73: 1637–1644.
Seeley WW, Crawford RK, Zhou J, Miller BL, Greicius MD. Neurodegenerative diseases target large-scale human brain networks. Neuron, 2009, 62: 42-52.