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Decreased, Calcium influx leads to BDNF, Reduced
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development leads to neurodegeneration with impairment in learning and memory in aging||adjacent||Low||Arthur Author (send email)||Open for citation & comment||WPHA/WNT Endorsed|
|Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities||adjacent||Low||Low||Agnes Aggy (send email)||Open for citation & comment||WPHA/WNT Endorsed|
Life Stage Applicability
Key Event Relationship Description
Mainly, NMDA receptor activation initiates Ca2+-dependent signaling events that regulate the expression of genes involved in regulation of neuronal function including bdnf (reviewed in Cohen and Greenberg, 2008). Inhibition of NMDA receptors results in low levels of Ca2+ and decreased transcription of BDNF and consequently to low level of BDNF protein production and release.
Evidence Supporting this KER
BDNF transcription is induced by Ca2+ entering through either L type voltage gated calcium channel (L-VGCC) (Tao et al., 1998) or NMDA receptor (Tabuchi et al., 2000; Zheng et al., 2011) that can last up to 6 h. BDNF IV that is the most studied among its different exons has been shown to bind three Ca2+ elements within the regulatory region (reviewed in Zheng et al., 2012). One of these Ca2+ elements binds to CREB facilitating transcription. However, more transcription factors rather than only CREB are implicated in the transcription process of BDNF such as NFAT (nuclear factor of activated T cell), MEF2 (myocyte enhancer factor 2) and NFκB (nuclear factor κB) (reviewed in Zheng et al., 2012). The activation of the relevant transcription factor is triggered by the initial activation of CaM kinase, cAMP/PKA and Ras/ERK1/2 pathways mediated by the elevated intracellular Ca2+. Interestingly, inhibitory studies targeting different elements of these pathways report reduction at mRNA BDNF levels (reviewed in Zheng et al., 2012).
In particular, exon IV BDNF mRNA transcription is regulated by a transcriptional silencer, methyl-CpG binding protein 2 (MeCP2), demonstrating that epigenetic alterations can also regulate BDNF transcription. Increase of intracellular Ca2+ levels phosphorylates MeCP2, which inactivates its repressor function and permits the transcription of BDNF exon IV (Chen et al., 2003; Greer and Greenberg, 2008; Tao et al., 2009; Zhou et al., 2006). Indeed, NMDA receptor activation has been shown to upregulate BDNF transcripts containing exon IV not only via Ca2+-dependent CREB but also through Ca2+ activation of MeCP2 transcription (Metsis et al., 1993; Shieh et al., 1998, Tao et al., 1998; Tabuchi et al., 2000; Chen et al., 2003; Jiang et al., 2005; Zheng et al., 2011), whereas NMDAR antagonists decrease BDNF exon IV expression (Zafra et al., 1991; Stansfield et al., 2012). Furthermore, BDNF mRNA is also targeted in different locations within the cell during the process of translation, depending on the promoter used (reviewed in Tongiorgi et al., 2006).
Interestingly, synaptic and extra-synaptic NMDARs have opposite effects on CREB: indeed calcium entry through synaptic NMDAR induced CREB activity and BDNF gene expression. In contrast, calcium entry through extra-synaptic NMDAR activates a general and dominant CREB shut-off pathway that blocked induction of BDNF expression (Hardingham et al., 2002).
Uncertainties and Inconsistencies
In a gene expression study, where gene analysis has been performed in the hippocampus derived from male or female rats fed with 1500 ppm Pb2+-containing chow for 30 days beginning at weaning, two molecular networks have been identified that were different between male and female treated rats. In these networks, CREB was the highly connected node, common for both networks (Schneider et al., 2011). However, no change has been reported in the expression of bdnf gene neither in male nor in female rats treated with Pb2+ (Schneider et al., 2011).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Chen WG, Chang Q, Lin Y, Meissner A, West AE, Griffith EC, Jaenisch R, Greenberg ME. (2003) Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science. 302: 885-889.
Cohen S, Greenberg ME. (2008) Communication between the synapse and the nucleus in neuronal development, plasticity and disease. Annu Rev Cell Dev Biol. 24: 183-209.
Greer PL, Greenberg ME. (2008) From synapse to nucleus: Calcium-dependent gene transcription in the control of synapse development and function. Neuron 59: 846-860.
Hardingham GE, Bading H. 2002. Coupling of extrasynaptic NMDA receptors to a CREB shut-off pathway is developmentally regulated. Biochim Biophys Acta 1600(1-2): 148-153.
Heaton MB, Mitchell JJ, Paiva M. (1999) Ethanol-induced alterations in neurotrophin expression in developing cerebellum: relationship to periods of temporal susceptibility. Alcohol Clin Exp Res. 23: 1637-1642.
Jiang X, Tian F, Mearow K, Okagaki P, Lipsky RH, Marini AM. (2005) The excitoprotective effect of N-methyl-D-aspartate receptors is mediated by a brain-derived neurotrophic factor autocrine loop in cultured hippocampal neurons. J Neurochem. 94: 713-722.
Metsis M, Timmusk T, Arenas E, Persson H. (1993) Differential usage of multiple brain-derived neurotrophic factor promoters in the rat brain following neuronal activation. Proc Natl Acad. Sci USA. 90: 8802-8806.
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.
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.
Schneider JS, Anderson DW, Sonnenahalli H, Vadigepalli R. (2011) Sex-based differences in gene expression in hippocampus following postnatal lead exposure. Toxicol Appl Pharmacol. 256: 179-190.
Schneider JS, Mettil W, Anderson DW. (2012). Differential Effect of Postnatal Lead Exposure on Gene Expression in the Hippocampus and Frontal Cortex. J Mol Neurosci. 47: 76-88.
Shieh PB, Hu SC, Bobb K, Timmusk T, Ghosh A. (1998) Identification of a signaling pathway involved in calcium regulation of BDNF expression. Neuron 20: 727–740.
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.
Tabuchi A, Nakaoka R, Amano K, Yukimine M, Andoh T, Kuraishi Y and Tsuda M. (2000) Differential activation of brain-derived neurotrophic factor gene promoters I and III by Ca2+ signals evoked via L-type voltage-dependent and N-methyl-D-aspartate receptor Ca2+ channels. J Biol Chem. 275: 17269-17275.Tao X, Finkbeiner S, Arnold DB, Shaywitz AJ, Greenberg ME. (1998) Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism. Neuron 20: 709-726.
Tao J, Hu K, Chang Q, Wu H, Sherman NE, Martinowich K, Klose RJ, Schanen C, Jaenisch R, Wang W, et al. (2009) Phosphorylation of MeCP2 at Serine 80 regulates its chromatin association and neurological function. Proc Natl Acad Sci USA. 106: 4882-4887.
Tongiorgi E, Domenici L, Simonato M. (2006) What is the biological significance of BDNF mRNA targeting in the dendrites? Clues from epilepsy and cortical development. Mol Neurobiol. 33: 17-32.
Toscano CD, Hashemzadeh-Gargari H, McGlothan JL, Guilarte TR. (2002) Developmental Pb2+ exposure alters NMDAR subtypes and reduces CREB phosphorylation in the rat brain. Brain Res Dev Brain Res. 139: 217-226.
Toscano CD, McGlothan JL, Guilarte TR. (2003) Lead exposure alters cyclic-AMP response element binding protein phosphorylation and binding activity in the developing rat brain. Brain Res. Dev. Brain Res. 145: 219-228.
Toscano CD, O'Callaghan JP, Guilarte TR. (2005) Calcium/calmodulin-dependent protein kinase II activity and expression are altered in the hippocampus of Pb2+-exposed rats. Brain Res. 1044: 51–58.
Zafra F, Castrén E, Thoenen H, Lindholm D. (1991) Interplay between glutamate and gamma-aminobutyric acid transmitter systems in the physiological regulation of brain-derived neurotrophic factor and nerve growth factor synthesis in hippocampal neurons. Proc Natl Acad Sci U S A. 88: 10037-10041.
Zheng F, Zhou X, Luo Y, Xiao H, Wayman G, Wang H. (2011) Regulation of brain-derived neurotrophic factor exon IV transcription through calcium responsive elements in cortical neurons. PLoS One 6: e28441.
Zheng F, Zhou X, Moon C, Wang H. (2012) Regulation of brain-derived neurotrophic factor expression in neurons. In J Pathophysiol Pharmacol 4: 188-200.
Zhou Z, Hong EJ, Cohen S, Zhao WN, Ho HY, Schmidt L, Chen WG, Lin Y, Savner E, Griffith EC, et al. (2006) Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation. Neuron 52: 255-269.