Upstream eventN/A, Neurodegeneration
Neuronal network function, Decreased
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
Key Event Relationship Description
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 relate to neural network dysfunction (Palop et al., 2007; 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 lead to decrease of neuronal network (Seeley et al., 2009).
Include consideration of temporal concordance here
- The effective concentration of DA causing decrease to 50% of control mean firing rate (MFR) values (EC50) in rat primary cultures (13-30 DIV) is 0.28 µM (Mack et al., 2014). Decrease of MFR has also been reported before by Hogberg et al. 2011, where mature cultures (28-35 DIV) have been exposed acutely to a wide range of concentrations of DA. The concentration of 0.5 μM DA significantly reduces MFR (77 %), the MBR (78 %) and the number of spikes per burst (71 %). Higher concentrations of DA (1 and 2 μM) also significantly decrease the MFR, whereas concentrations up to 0.1 μM of DA do not cause any effect on MFR (Hogberg et al., 2011). In primary rat cortical neurons (12-22 DIV), DA (50 µM) has been reported to reduce MFR by more than 90% (McConnell et al., 2012).
- Ten-minute exposure of rat hippocampal CA1 region slices to 400 nM DA causes depression of fEPSP (Qiu et al., 2009). After 1 h washout, fEPSP gradually has been recovered. DA-potentiated slices have shown also less tetanus-induced LTP compared with control slices when tested with either original stimulus or reset stimulus (Qiu et al., 2009). In addition, prolonged application of 400 nM DA reversibly depresses CA1 fEPSP and impairs the subsequent development of tetanus LTP (Qiu et al., 2009).
Uncertainties and Inconsistencies
Administration of high dose DA (4.4 mg/kg) to adult male Sprague-Dawley rats causes elevation of electrocorticogram (ECoG) beginning 30 min post injection, whereas at low dose (2.2 mg/kg) ECoG becomes elevated after 110 min (Binienda et al., 2011).
Quantitative Understanding of the Linkage
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 DA (1 mM) (Lee et al., 2009). However, in crayfish (Procambarus clarkia) the same concentration of DA 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.
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.
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 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. 2007. 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.
Seeley WW, Crawford RK, Zhou J, Miller BL, Greicius MD. Neurodegenerative diseases target large-scale human brain networks. Neuron. 2009. 62:42-52.