Upstream eventN/A, Cell injury/death
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities||non-adjacent||Low|
Life Stage Applicability
Key Event Relationship Description
Under physiological conditions, in the developing nervous system, apoptosis occurs during the process of synaptogenesis, where competition leads to the loss of excess neurons and to the connection of the appropriate neurons (Buss et al., 2006; Mennerick and Zorumski, 2000; Oppenheim, 1991). However, when a stressor increases the number of apoptotic cells this KE has a negative effect on synaptogenesis as the reduced number of neurons (besides the ones that have been already eliminated through the physiological process of apoptosis) provides limited dendritic fields for receiving synaptic inputs from incoming axons. At the same time the loss of neurons also means that there are less axons to establish synaptic contacts (Olney, 2014), leading to reduced synaptogenesis and neuronal networking.
Evidence Supporting this KER
Recently, Dekkers et al. 2013 have reviewed how under physiological conditions components of the apoptotic machinery in developing brain regulate synapse formation and neuronal connectivity. For example, caspase activation is known to be required for axon pruning during development to generate neuronal network (reviewed in Dekkers et al., 2013). Experimental work carried out in Drosophila melanogaster and in mammalian neurons shows that components of apoptotic machinery are involved in axonal degeneration that can consequently interfere with synapse formation (reviewed in Dekkers et al., 2013). Furthermore, Bax mutant mice studies indicate that the lack of this pro-apoptotic protein BAX leads to disruption of intrinsically photosensitive retinal ganglion cells spacing and dendritic stratification that affects synapse localization and function (Chen et al., 2013).
Include consideration of temporal concordance here
Synaptogenesis and refinement of the cortical network precedes the programmed cells death of neurons during development (Innocenti and Price, 2005).
Pb2+: Elevated blood Pb2+ concentrations that have been evident in new-born rats prenatally exposed to 30 or 200 mg/l Pb2+ caused postnatally delay in synaptogenesis (McCauley et al., 1982). In this study, Pb2+ treatment depresses synaptic counts in pups of PND 11 to 15 but not in older pups (McCauley et al., 1982). In rat hippocampal primary cultures, Pb2+ treatment has no effect on PSD95 puncta density nor has any effect on Synapsin Ia/b total gray value, puncta density, and integrated intensity but only reduces the phosphorylation of Synapsin Ia/b (Stansfield et al., 2012). Pb2+ exposure also represses the expression of presynaptic vesicular proteins implicated in neurotransmitter release, such as synaptobrevin (VAMP1) and synaptophysin (SYN) (Neal et al., 2010). In mouse ESCs cultured in 3D aggregates, the treatment with 0.1 µM Pb2+ causes around 25% of cell loss that is not attributed to apoptosis as no change in caspase 3 levels has been detected (Sánchez-Martín et al., 2013). In the same study but in an in vivo model, Pb2+ causes downregulation of Syn1 gene expression in the hippocampus of male offspring (PND 60) derived from female mice exposed to 0 or 3 ppm of lead acetate in drinking water from 8 weeks prior to mating, through gestation and until PND 10 (Sánchez-Martín et al., 2013).
Uncertainties and Inconsistencies
In adult nervous system, the role of apoptotic machinery in axon pruning and synapse elimination, which are necessary to refine mature neuronal network has been extensively studied (reviewed in Hyman and Yuan, 2012), whereas in developing nervous system the regulatory importance of apoptotic machinery in synapse formation and function is less clear (reviewed in Dekkers et al., 2013).
Quantitative Understanding of the Linkage
Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?
No enough data is available to address the questions above.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Experiments have been conducted both in Drosophila melanogaster and in mammals in order to elucidate the relationship between components of apoptotic machinery and synaptogenesis (reviewed in Dekkers et al., 2013).
Buss RR, Sun W, Oppenheim RW. (2006) Adaptive roles of programmed cell death during nervous system development. Annu Rev Neurosci. 29: 1-35.
Chen SK, Chew KS, McNeill DS, Keeley PW, Ecker JL, Mao BQ, Pahlberg J, Kim B, Lee SC, Fox MA, Guido W, Wong KY, Sampath AP, Reese BE, Kuruvilla R, Hattar S. (2013) Apoptosis regulates ipRGC spacing necessary for rods and cones to drive circadian photoentrainment. Neuron 77: 503-515.
Dekkers MPJ, Nikoletopoulou V, Barde Y-A. (2013) Death of developing neurons: New insights and implications for connectivity. J Cell Biol. 203: 385-393.
Hyman BT, Yuan J. (2012) Apoptotic and non-apoptotic roles of caspases in neuronal physiology and pathophysiology. Nat Rev Neurosci 13: 395-406.
Innocenti, GM, Price DJ. (2005) Exuberance in the development of cortical networks. Nat Rev Neurosci. 6: 955-965.
McCauley PT, Bull RJ, Tonti AP, Lukenhoff SD, Meister MV, Doerger JU, Stober JA. (1982) The effect of prenatal and postnatal lead exposure on neonatal synaptogenesis in rat cerebral cortex. J Toxicol Environ Health 10: 639-651.
Mennerick S, Zorumski CF. (2000) Neural activity and survival in the developing nervous system. Mol Neurobiol. 22: 41-54.
Neal AP, Stansfield KH, Worley PF, Thompson RE, Guilarte TR. (2010) Lead exposure during synaptogenesis alters vesicular proteins and impairs vesicular release: Potential role of NMDA receptor-dependent BDNF signaling. Toxicol Sci. 116: 249-263.
Olney JW. (2014) Focus on apoptosis to decipher how alcohol and many other drugs disrupt brain development front. Pediatr. 2: 81.
Oppenheim RW. (1991). Cell death during development of the nervous system. Annu Rev Neurosci. 14: 453-501.
Sánchez-Martín FJ, Fan Y, Lindquist DM, Xia Y, Puga A. (2013) Lead Induces Similar Gene Expression Changes in Brains of Gestationally Exposed Adult Mice and in Neurons Differentiated from Mouse Embryonic Stem Cells. PLoS One 8: e80558.
Stansfield KH, Pilsner JR, Lu Q, Wright RO, Guilarte TR. (2012) Dysregulation of BDNF-TrkB signaling in developing hippocampal neurons by Pb(2+): implications for an environmental basis of neurodevelopmental disorders. Toxicol Sci. 127: 277-295.