Upstream eventReduced, Presynaptic release of glutamate
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
The presynaptic release of glutamate causes activation of NMDA receptors and initiates synaptogenesis through activation of downstream signalling pathways required for synapse formation (reviewed in Ghiani et al., 2007). Lack or reduced release of glutamate affects the transcription and translation of molecules required in synaptogenesis (reviewed in Ghiani et al., 2007).
Evidence Supporting this KER
The NMDA receptor activation by glutamate during development increases calcium influx, which acts as a secondary signal. Eventually, immediate early genes (IEG) activation is triggered by transcription factors and the proteins required for synapse formation are produced (reviewed in Ghiani et al., 2007).
Glutamate released from entorhinal cortex neurons has been shown to promote synaptogenesis in developing targeted hippocampal neurons (Mattson et al., 1988). Similarly, glutamate has been found to regulate synaptogenesis in the developing visual system of frogs (Cline and Constantine-Paton, 1990).
The ratio of synaptic NR2B over NR2A NMDAR subunits controls spine motility and synaptogenesis, and it has been suggested a structural role for the intracellular C terminus of NR2 in recruiting the signaling and scaffolding molecules necessary for proper synaptogenesis (Gambrill and Barria, 2011).
Include consideration of temporal concordance here
There is no direct evidence linking reduced presynaptic release of glutamate to decreased synaptogenesis as they have not been ever measured both in the same study after exposure to stressors. However, there are findings that strongly link reduced presynaptic release of glutamate to LTP.
Indeed, measures of presynaptic function at glutamatergic synapses in chronically exposed animals have produced results that can be related to the effects of Pb2+ on glutamate and LTP. Focal perfusion of high K+ is used to measure glutamate release and define the Ca+2-dependent and Ca+2-independent components by inclusion or removal of Ca+2 from the perfusion fluid. Animals exposed to 0.2% Pb2+ cause decrease in K+-evoked hippocampal glutamate release, which is an important factor in the elevated threshold and diminishes magnitude of hippocampal LTP (Gilbert et al., 1996, 1999; Lasley and Gilbert, 1996). Furthermore, the same research group showed that chronic exposure to 0.2% Pb2+ diminishes only the K+-stimulated increase in total extracellular glutamate compared to that in control but not in animals under Ca+2-free conditions, suggesting that the exposure-induced decrease in total glutamate release is due to Pb2+ -related decrements in the Ca+2-dependent component.
In animals exhibiting blood Pb2+ levels of 30-40 μg/100 ml, the perforant path stimulation to induce paired-pulse facilitation in dentate gyrus, which is a measure that is primarily mediated by enhanced glutamate release, is reduced (Lasley and Gilbert, 1996; Ruan et al., 1998). Microdialysis experiment in animals with the same Pb2+ values show diminished depolarization-induced hippocampal glutamate release (Lasley and Gilbert, 1996; Lasley et al., 1999).
In another study, rats continuously exposed to 0.1–0.5% Pb2+ in the drinking water beginning at gestational day 15-16 show decrease in total K+-stimulated hippocampal glutamate release (Lasley and Gilbert, 2002). Maximal effects have been seen in the 0.2% group (blood Pb = 40 μg/100 ml). However, these effects have been less evident in the 0.5% group and are no longer present in the 1.0% Pb2+ group (Lasley and Gilbert, 2002). The same finding was found in hippocampal cultures and brain slices acutely exposed to Pb2+ (Braga et al., 1999; Xiao et al., 2006).
More recently, Pb2+ has also been shown to decrease the levels of the vesicular proteins synaptophysin and synaptobrevin and inhibit vesicular release (Neal et al., 2010). Furthermore the same group has reported that chronic in vivo exposure to Pb2+ during development results in a marked inhibition of Schaffer-collateral-CA1 synaptic transmission by inhibiting vesicular release of glutamate, an effect that is not associated with a persistent change in presynaptic calcium entry (Zhang et al., 2015).
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
Braga MFM, Pereire EFR, Albuquerque EX. (1999) Nanomolar concentration of lead inhibit glutamatergic and GABAergic transmission in hippocampal neurons. Brain Res. 826: 22–34.
Cline HT, Constantine-Paton M. (1990) NMDA receptor agonist and antagonists alter retinal ganglion cell arbor structure in the developing frog retinotectal projection. J Neurosci. 10: 1197-1216.
Gambrill AC, Barria A. (2011) NMDA receptor subunit composition controls synaptogenesis and synapse stabilization. Proc Natl Acad Sci U S A. 108: 5855-5860.
Ghiani CA, Beltran-Parrazal L, Sforza DM, et al. (2007) Genetic program of neuronal differentiation and growth induced by specific activation of NMDA receptors. Neurochem Res. 32: 363-376.
Gilbert ME, Mack CM, Lasley SM. (1996) Chronic developmental lead (Pb++) exposure increases the threshold for long-term potentiation in the rat dentate gyrus in vivo. Brain Res. 736: 118–124.
Gilbert ME, Mack CM, Lasley SM. (1999a) The influence of developmental period of lead exposure on long-term potentiation in the rat dentate gyrus in vivo. Neurotoxicology 20: 57–69.
Lasley SM, Gilbert ME. (1996) Presynaptic glutamatergic function in dentate gyrus in vivo is diminished by chronic exposure to inorganic lead. Brain Res. 736: 125–134.
Lasley SM, Gilbert ME. (2002) Rat hippocampal glutamate and GABA release exhibit biphasic effects as a function of chronic lead exposure level. Toxicol Sci. 66: 139-147.
Lasley SM, Green MC, Gilbert ME (1999). Influence of exposure period on in vivo hippocampal glutamate and GABA release in rats chronically exposed to lead. Neurotoxicology 20: 619–629.
Mattson MP, Lee RE, Adams ME, Guthrie PB, Kater SB. (1988) Interactions between entorhinal axons and target hippocampal neurons: a role for glutamate in the development of hippocampal circuitry. Neuron 1: 865-876.
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.
Ruan DY, Chen JT, Zhao C, Xu YZ, Wang M, Zhao WF. (1998) Impairment of long-term potentiation and paired-pulse facilitation in rat hippocampal dentate gyrus following developmental lead exposure in vivo. Brain Res. 806, 196–201.
Xiao C, Gu Y, Zhou CY, Wang L, Zhang MM, Ruan DY, et al. Lead impairs GABAergic synaptic transmission in rat hippocampal slices: a possible involvement of presynaptic calcium channels. Brain Res. 2006; 1088: 93–100.
Zhang XL, Guariglia SR, McGlothan JL, Stansfield KH, Stanton PK, Guilarte TR. (2015) Presynaptic mechanisms of lead neurotoxicity: effects on vesicular release, vesicle clustering and mitochondria number. PLoS One. 10(5):e0127461.