Upstream eventAberrant, Dendritic morphology
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||adjacent||Low|
Life Stage Applicability
Key Event Relationship Description
It is well-established that loss of dendritic spine density and dendrite branch complexity leads to loss of synapse formation. Indeed, huge amount of research has been performed on dendrite arbour, dendritic spines and the molecular components of these structures that led to the elucidation of their role in higher order brain functions, including learning and memory (reviewed in Sjöström et al., 2008).
Evidence Supporting this KER
It has been proved that the appearance of extensive dendritic arbor and new spines coincides with synapse formation (Zito et al., 2004). Zhang and Benson (2001) have investigated the role of actin (the main component of dendritic spines) during the early stages of neuronal development by introducing an actin depolymerization protein named latrunculin A and conducting fluorescent imaging of synapse formation. At the early stages of neuronal development, it has been reported that the depolymerisation of filamentous actin (F-actin) significantly reduces the number of stable synapses and the presence of postsynaptic proteins (PSD-95, neuroligins, and Bassoon). Most importantly, pre- and postsynaptic vesicles needed for synaptogenesis have not been found at contact sites as a result of depolymerisation of F-actin (Zhang and Benson, 2001). Furthermore, synapsin I-deficient neurons have been shown to be unable to form synapses during the first week in culture even after establishing axon-dendritic contacts (Ferreira et al., 1996).
Include consideration of temporal concordance here
Many studies have indicated that synaptogenesis and spine formation happen in any order, meaning that not always synaptogenesis follows the spine formation but it can also happen the other way around (Bhatt et al., 2009; McAllister, 2007; Okabe et al., 2001).
Pb2+: Newborn rats exposed to 10 mg/ml of lead acetate from PND 2 up to PND 20 and 56 demonstrate significant decrease in the spine density as shown in Golgi staining of hippocampal pyramidal neurons of the CA1 region (Kiraly and Jones, 1982). Rat pups from parents exposed to 2 mM PbCl2 3 weeks before mating until their weaning (pre-weaning Pb2+) and weaned pups exposed to 2 mM PbCl2 for 9 weeks (post-weaning Pb2+) were assessed for the number of synapses after Morris water maze (MWM) on PND 91 (Xiao et al., 2014). The number of synapses in pre-weaning Pb2+ group increased significantly, but it was less compared to control group (p<0.05). Similarly, the number of synapses in post-weaning Pb2+ group was less than that of control group, although before MWM the number of synapses was almost the same between post-weaning Pb2+ and control groups. In both pre-weaning Pb2+ and post-weaning Pb2+ groups, synaptic structural parameters such as thickness of postsynaptic density, length of synaptic active zone and synaptic curvature increased whereas width of synaptic cleft decreased compared to controls, suggesting disturbance of synaptic structural plasticity (Xiao et al., 2014).
Pb2+ has been shown to decrease the levels of the vesicular proteins synaptophysin and synaptobrevin in vitro (Neal et al., 2010).
Uncertainties and Inconsistencies
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
Bhatt DH, Zhang S, Gan WB. (2009). Dendritic Spine Dynamics. Ann Rev Physiol. 71: 261-282.
Ferreira A, Li L, Chin LS, Greengard P, Kosik KS. (1996) Postsynaptic element contributes to the delay in synaptogenesis in synapsin I-deficient neurons. Mol Cell Neurosci. 8: 286-299.
Kiraly E, Jones DG. (1982) Dendritic spine changes in rat hippocampal pyramidal cells after postnatal lead treatment: A Golgi study. Exp Neurol. 77: 236-239.
McAllister AK. (2007) Dynamic aspects of CNS synapse formation. Ann Rev of Neurosc. 30: 425-450.
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.
Okabe S, Miwa A, Okado H. (2001) Spine formation and correlated assembly of presynaptic and postsynaptic molecules. J Neurosci. 21: 6105-6114.
Sjöström PJ, Rancz EA, Roth A, Häusser M. (2008) Dendritic excitability and synaptic plasticity. Physiol Rev. 88: 769-840.
Xiao Y, Fu H, Han X, Hu X, Gu H, Chen Y, Wei Q, Hu Q. (2014) Role of synaptic structural plasticity in impairments of spatial learning and memory induced by developmental lead exposure in Wistar rats. PLoS One. 23;9(12):e115556.
Zhang W, Benson DL. (2001) Stages of synapse development defined by dependence on F-actin. J Neurosci. 21: 5169-5181.
Zito K, Knott G, Shepherd GM, Shenolikar S, Svoboda K. (2004) Induction of spine growth and synapse formation by regulation of the spine actin cytoskeleton. Neuron 44: 321-334.