Upstream eventBDNF, Reduced
Reduced, Presynaptic release of glutamate
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Directness||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||indirectly leads to||Weak|
Life Stage Applicability
How Does This Key Event Relationship Work
BDNF, acting via its specific presynaptic receptor TrkB, has been shown to increase excitatory synaptic transmission by triggering presynaptic glutamate release in hippocampal cultures as well as in hippocampal and cortical slices (Lessmann et al., 1994; Kang and Schuman, 1995; Carmignoto et al., 1997; Mohajerani et al., 2007).
Weight of Evidence
Experimentally, it has been shown that presynaptically, BDNF enhances glutamate release and increases the frequency of mEPSCs in hippocampal neurons of rat (Lessmann and Heumann, 1998; Takei et al., 1998; Minichiello, 2009). It has been reported that BDNF rapidly induces glutamate transporter-mediated glutamate release via phospholipase C-γ (PLC-γ)/Ca2+ signaling and that antidepressants enhance PLC-γ/Ca2+ signaling leading to reduced levels of BDNF that cause decreased glutamate release (Numakawa et al., 2002; Yagasaki et al., 2006).
Empirical Support for Linkage
Include consideration of temporal concordance here
- In cortical cultured neurons obtained from PND 2-3 rat pups, BDNF fails to induce glutamate release at DIV 3 and 4. However, after 5 days in vitro culture or more (DIV 6-9), BDNF (100 ng/ml) induces significant glutamate release (2-2.8 fold) within 1 min after exogenous application (Numakawa et al., 2002).
- It has been shown that there is a dose-dependent effect of BDNF on the glutamate release. The glutamate release is initially observed at 5 ng/ml BDNF and reaches a plateau at 100 ng/ml (Numakawa et al., 2002).
- No studies have been found in the literature measuring both KEs after exposure to the stressors. Interestingly, proton magnetic resonance spectroscopy in adults with childhood lead exposure shows decrease in a composite of glutamate and glutamine in vermis and in parietal white matter of the brain (Cecil et al., 2011).
Uncertainties or Inconsistencies
Recently, in heterozygous BDNF-knockout (BDNF+/−) mice it has been demonstrated that the reduced BDNF levels did not affect presynaptic glutamate release (Meis et al., 2012).
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.
Evidence Supporting Taxonomic Applicability
Carmignoto G, Pizzorusso T, Tia S, Vicini S. (1997) Brain-derived neurotrophic factor and nerve growth factor potentiate excitatory synaptic transmission in the rat visual cortex. J Physiol. 498: 153-164.
Cecil KM, Dietrich KN, Altaye M, Egelhoff JC, Lindquist DM, Brubaker CJ, Lanphear BP. (2011) Proton magnetic resonance spectroscopy in adults with childhood lead exposure. Environ Health Perspect. 119: 403-408.
Kang H, Schuman EM. (1995) Long-lasting neurotrophin-induced enhancement of synaptic transmission in the adult hippocampus. Science. 267: 1658-1662.
Lessmann V, Gottmann K, Heumann R. (1994) BDNF and NT-4/5 enhance glutamatergic synaptic transmission in cultured hippocampal neurones. Neuroreport 6: 21-25.
Lessmann V, Heumann R. (1998) Modulation of unitary glutamatergic synapses by neurotrophin-4/5 or brain-derived neurotrophic factor in hippocampal microcultures: presynaptic enhancement depends on pre-established paired-pulse facilitation. Neuroscience 86: 399-413.
Meis S, Endres T, Lessmann V. (2012) Postsynaptic BDNF signalling regulates long-term potentiation at thalamo-amygdala afferents. J Physiol. 590: 193-208.
Minichiello L. (2009) TrkB signalling pathways in LTP and learning. Nat Rev Neurosci. 10: 850-860.
Mohajerani MH, Sivakumaran S, Zacchi P, Aguilera P, Cherubini E. (2007) Correlated network activity enhances synaptic efficacy via BDNF and the ERK pathway at immature CA3 CA1 connections in the hippocampus. Proc Natl Acad Sci U S A. 104: 13176-13181.
Numakawa T, Yamagishi S, Adachi N, Matsumoto T, Yokomaku D, Yamada M, Hatanaka H. (2002) Brain-derived neurotrophic factor-induced potentiation of Ca2+ oscillations in developing J Biol Chem. 277: 6520-6529.
Takei N, Numakawa T, Kozaki S, Sakai N, Endo Y, Takahashi M, et al. (1998) Brain-derived neurotrophic factor induces rapid and transient release of glutamate through the non-exocytotic pathway from cortical neurons. J Biol Chem. 273: 27620-27624.
Yagasaki Y, Numakawa T, Kumamaru E, Hayashi T, Su TP, Kunugi H. (2006) Chronic antidepressants potentiate via sigma-1 receptors the brain-derived neurotrophic factor-induced signaling for glutamate release. J Biol Chem. 281: 12941-12949.