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Cell injury/death 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|
|Binding of electrophilic chemicals to SH(thiol)-group of proteins and /or to seleno-proteins involved in protection against oxidative stress during brain development leads to impairment of learning and memory||adjacent||Moderate||Brendan Ferreri-Hanberry (send email)||Under development: Not open for comment. Do not cite||EAGMST Under Review|
Life Stage Applicability
|All life stages|
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). 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. The ability of a neuron to communicate is based on neural network formation that relies on functional synapse establishment (Colón-Ramos, 2009). The main roles of synapses are the regulation of intercellular communication in the nervous system, and the information flow within neural networks. The connectivity and functionality of neural networks depends on where and when synapses are formed. Therefore, the decreased synapse formation due to cell death during the process of synaptogenesis is critical and leads to decrease of neural network formation and function in the adult brain.
Synaptic transmission and plasticity require the integrity of the anatomical substrate. The connectivity of axons emanating from one set of cells to post-synaptic side of synapse on the dendrites of the receiving cells must be intact for effective communication between neurons. Changes in the placement of cells within the network due to delays in neuronal migration, the absence of a full formation of dendritic arbors and spine upon which synaptic contacts are made, and the lagging of transmission of electrical impulses due to insufficient myelination will individually and cumulatively impair synaptic function.
Therefore, chemicals inducing neuronal cell death by apoptosis or necrosis, or interfering with a particular system of neurotransmitters, will alter network structure and function.
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).
Neuronal network formation and function are established via the process of synaptogenesis. 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). The brain electrical activity dependence on synapse formation is critical for proper neuronal communication.
Alterations in synaptic connectivity lead to refinement of neuronal networks during development (Cline and Haas, 2008). Indeed, knockdown of PSD-95 arrests the functional and morphological development of glutamatergic synapses (Ehrlich et al., 2007).
Studies of the last 30 years demonstrated that astrocytes possess functional receptors for neurotransmitters and respond to their stimulation via release of gliotransmitters, including glutamate. These findings have led to a new concept of neuron–glia intercommunication where astrocytes play an unsuspected dynamic role by integrating neuronal inputs and modulating synaptic activity (Rossi and Volterra, 2009). According to the concept termed "tripartite synapse", the emerging view is that brain function actually arises from the coordinated activity of a network comprising both neurons and astrocytes. Furthermore, myelinating glial cells are well-known to insulate axons and to speed up action potential propagation. Be it motor skill learning or social behaviors in higher vertebrates, proper myelination is critical in shaping brain functions. Neurons rely on their myelinating partners not only for setting conduction speed, but also for regulating the ionic environment and fueling their energy demands with metabolites. Also, long-term axonal integrity and neuronal survival are maintained by oligodendrocytes and loss of this well-coordinated axon-glial interplay contributes to brain diseases (Saab and Nave, 2017). Therefore, reduction in glial cell number and/or reduction in myelination of axons, will very much impact the neural network function.
Uncertainties and Inconsistencies
Ogawa et al. (2011) reported decreased apoptosis and an increase in the number of Gabaergic interneurons in the dentate gyrus of Sprague-Dawley pups either maternally exposed to acrylamide or directly injected with acrylamide.
Although it appears evident that a decrease in cell number, in dendritic arborization or in axonal growth, as well as synapse alterations may lead to decreased neuronal network formation and function, the exact mechanism remain to be elucidated.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Support for the link between cell injury/death and decreased neuronal network formation and function can be found in rat, mouse and minnow. (for references, see empirical evidences)
Buss, R.R., Sun, W., Oppenheim, R.W., 2006. Adaptive roles of programmed cell death during nervous system development. Annu Rev Neurosci 29, 1-35.
Chen, S.K., Chew, K.S., McNeill, D.S., Keeley, P.W., Ecker, J.L., Mao, B.Q., Pahlberg, J., Kim, B., Lee, S.C., Fox, M.A., Guido, W., Wong, K.Y., Sampath, A.P., Reese, B.E., Kuruvilla, R., Hattar, S., 2013. Apoptosis regulates ipRGC spacing necessary for rods and cones to drive circadian photoentrainment. Neuron 77, 503-515.
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.
Colon-Ramos, D.A., 2009. Synapse formation in developing neural circuits. Curr Top Dev Biol 87, 53-79.
Dekkers, M.P., Nikoletopoulou, V., Barde, Y.A., 2013. Cell biology in neuroscience: Death of developing neurons: new insights and implications for connectivity. J Cell Biol 203, 385-393.
Ehrlich, I., Klein, M., Rumpel, S., Malinow, R., 2007. PSD-95 is required for activity-driven synapse stabilization. Proc Natl Acad Sci U S A 104, 4176-4181.
Falluel-Morel, A., Sokolowski, K., Sisti, H.M., Zhou, X., Shors, T.J., Dicicco-Bloom, E., 2007. Developmental mercury exposure elicits acute hippocampal cell death, reductions in neurogenesis, and severe learning deficits during puberty. J Neurochem 103, 1968-1981.
Ferraro, L., Tomasini, M.C., Tanganelli, S., Mazza, R., Coluccia, A., Carratu, M.R., Gaetani, S., Cuomo, V., Antonelli, T., 2009. Developmental exposure to methylmercury elicits early cell death in the cerebral cortex and long-term memory deficits in the rat. Int J Dev Neurosci 27, 165-174.
Jacob, S., Thangarajan, S., 2017. Effect of Gestational Intake of Fisetin (3,3',4',7-Tetrahydroxyflavone) on Developmental Methyl Mercury Neurotoxicity in F1 Generation Rats. Biol Trace Elem Res 177, 297-315.
Mennerick, S., Zorumski, C.F., 2000. Neural activity and survival in the developing nervous system. Mol Neurobiol 22, 41-54.
Nagashima, K., 1997. A review of experimental methylmercury toxicity in rats: neuropathology and evidence for apoptosis. Toxicol Pathol 25, 624-631.
Nagashima, K., Fujii, Y., Tsukamoto, T., Nukuzuma, S., Satoh, M., Fujita, M., Fujioka, Y., Akagi, H., 1996. Apoptotic process of cerebellar degeneration in experimental methylmercury intoxication of rats. Acta Neuropathol 91, 72-77.
Ogawa, B., Ohishi, T., Wang, L., Takahashi, M., Taniai, E., Hayashi, H., Mitsumori, K., Shibutani, M., 2011. Disruptive neuronal development by acrylamide in the hippocampal dentate hilus after developmental exposure in rats. Arch Toxicol 85, 987-994.
Olney, J.W., 2014. Focus on apoptosis to decipher how alcohol and many other drugs disrupt brain development. Front Pediatr 2, 81.
Oppenheim, R.W., 1991. Cell death during development of the nervous system. Annu Rev Neurosci 14, 453-501.
Perea, G., Navarrete, M., Araque, A., 2009. Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci 32, 421-431.
Rodier, P.M., 1995. Developing brain as a target of toxicity. Environ Health Perspect 103 Suppl 6, 73-76.
Rossi, D., Volterra, A., 2009. Astrocytic dysfunction: insights on the role in neurodegeneration. Brain Res Bull 80, 224-232.
Saab, A.S., Nave, K.A., 2017. Myelin dynamics: protecting and shaping neuronal functions. Curr Opin Neurobiol 47, 104-112.
Wang, Y.T., Lin, H.C., Zhao, W.Z., Huang, H.J., Lo, Y.L., Wang, H.T., Lin, A.M., 2017. Acrolein acts as a neurotoxin in the nigrostriatal dopaminergic system of rat: involvement of alpha-synuclein aggregation and programmed cell death. Sci Rep 7, 45741.