Upstream eventBDNF, Reduced
Aberrant, 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||non-adjacent||Low|
Life Stage Applicability
Key Event Relationship Description
The dendritically synthesized BDNF when secreted activates tyrosine kinase B (TrkB) receptors that induce the synthesis of a number of proteins involved in the development of proper dendritic spine morphology.
Evidence Supporting this KER
After activation of tyrosine kinase B (TrkB) receptors by BDNF proteins such as Arc, Homer2, LIMK1 (Kang and Schuman, 1996, Schratt et al., 2004 and Yin et al., 2002) that are known to promote actin polymerization and consequently enlargement of spine heads (Sala et al., 2001) are released. Recently, it has been shown that BDNF promotes dendritic spine formation by interacting with Wnt signaling. Indeed, Wnt signaling inhibition in cultured cortical neurons caused disruption in dendritic spine development, reduction in dendritic arbor size and complexity and blockage of BDNF-induced dendritic spine formation and maturation (Hiester et al., 2013).
In addition, it has been shown that the inhibition of BDNF synthesis reduces the size of spine heads and impairs LTP (An et al., 2008; Waterhouse and Xu, 2009). BDNF has been characterized as a critical factor in promoting dendritic morphogenesis in various types of neurons (reviewed in Jan and Jan, 2010; Park and Poo, 2013).
BDNF that is synthesised in dendrites is known to regulate the morphology of spines (Tyler and Pozzo-Miller, 2003; An et al., 2008). For example, spines in the absence of spontaneous electrical activity are significantly smaller than normal (Harvey et al., 2008). On the other hand, simultaneous electrical activity and glutamate release increase the size of the spine head, which has been shown to be dependent on BDNF (Tanaka et al., 2008).
Mice harboring the Val66Met mutation of Bdnf gene show dendritic arborization defects in the hippocampus. Interestingly, human subjects with the Val66Met SNP demonstrate similar anatomical features (reviewed in Cohen and Greenberg, 2008).
More targeted studies have shown that, within the physiological range of expression, dendritic spine density is tightly regulated by BDNF in the dentate gyrus but not in CA1 pyramidal cells (Alexis and Stranahan, 2011).
Include consideration of temporal concordance here
Exposure of rat hippocampal neurons in culture to BDNF causes increase in cypin mRNA and protein levels, which is a known guanine deaminase that activates dendritic arborisation. This increase of cypin induced by BDNF appears after 72 h but not at earlier time points (Kwon et al., 2011), meaning that BDNF has to act first in order to stimulate dendritic arbor formation.
Pb2+: The first hint for involvement of Pb2+ in dendritic morphology was described by Alfano and Petit. 1982. They have demonstrated reduction in the length of dendritic processes and the number of dendritic branches in hippocampal dentate granule cells after developmental Pb2+ exposure of Long-Evans hooded rat pups (Alfano and Petit, 1982). More recently, it has been shown that the chronic exposure of rats to environmentally relevant levels (Pb2+ blood levels 25.8 ± 1.28 μg/dL) during early life alters cell morphology in the dentate gyrus as immature granule cells immunolabeled with doublecortin display aberrant dendritic morphology (Verina et al., 2007).
Exposure of rats to Pb2+ that initiated at embryonic phase and terminated at PND 21 have revealed that at PND 14 (Pb2+ concentration in the hippocampus 0.249±0.06 µg/g) and PND 21 (Pb2+ concentration in the hippocampus 0.471±0.11 µg/g) the number of dendritic spine on hippocampal CA1 area decreases by 32.83% and 24.11%, respectively (Hu et al., 2014). The length-density of the doublecortin-positive apical dendrites in the outer portion of the dentate gyrus molecular layer has been found significantly decreased up to 36% in chronically exposed rats to environmentally relevant levels of Pb2+ (Pb2+ blood levels 25.8 ± 1.28 μg/dL) (Verina et al., 2007). In another in vivo study, lower blood levels of Pb2+ (10 ± 1.28 μg/dL) in similar age of rats has led to significant decrease of BDNF concentration (pg/mg protein) that is 39% in forebrain cortex and 29% in hippocampus (Baranowska-Bosiacka et al., 2013).
In cultured rat hippocampal neurons, low levels of Pb2+ (0.1 and 1 µM) cause reduction of dendritic spine density in a dose-dependent manner (Hu et al., 2014). In a similar in vitro model, exposure to 1 μM Pb2+ for 5 days during the period of synaptogenesis (DIV7–DIV12), significantly reduces proBDNF protein and extracellular levels of mBDNF (Neal et al., 2010). When mouse embryonic stem cells are differentiated into neurons, exposure to lead (II) acetate causes reduction in the percentage of microtubule-associated protein 2 (MAP-2)-positive cells and in the mRNA levels of MAP-2 in a dose-dependent manner (Baek et al., 2011). Similar effects were found in dissociated cells derived from neuro-spheres generated from neural stem cells (NSCs) originating from E15 rat cortex (CX), striatum (ST) or ventral mesencephalon (VM) exposed for 7 days to lead acetate (Huang and Schneider, 2004). More specifically, lead exposure (0.1–10 μM) decreases MAP-2-positive cells of ST and VM-derived NSCs, whereas there is no effect in CX-derived NSCs. VM-derived NSCs have the greatest sensitivity to the inhibitory effects of lead exposure causing 25% decrease in MAP-2-positive cells at 0.1 μM and almost 50% at 10 μM (Huang and Schneider, 2004).
|Stressor||Experimental Model||Tested concentrations||Exposure route||Exposure duration||Release of BDNF, Reduced (KE up) (measurements, quantitative if available)||Dendritic morphology, Aberrant (KE down) (measurements, quantitative if available)||References|
|Lead||SD rats||SD rat dams were given drinking distilled water and lead water (250 ppm lead acetate in distilled water, 30 ml/day). The lead-exposed pups acquired lead via milk of dams during lactation period. In vivo experiments were carried out at the age of 14 and 21 days. PND 14 (Pb2+ concentration in the hippocampus 0.249±0.06 µg/g) and PND 21 (Pb2+ concentration in the hippocampus 0.471±0.11 µg/g)||in utero and per os||Exposure of rats to Pb2+ that initiated at embryonic phase and terminated at PND 14 and 21||Dendritic spine on hippocampal CA1 area decreases by 32.83% (PND 14) and 24.11% (PND 21)||Hu et al., 2014|
|Lead||Long-Evans rats||Female rats (225–250 g) were fed 0 or 1500-ppm Pb2+ acetate (Pb2+ blood levels 25.8 ± 1.28 µg/dL)||in utero and per os||Feeding of the Pb2+-containing and control diets was initiated 10 days before breeding females to untreated Long-Evans male rats. Dams were maintained on their respective diets during gestation and lactation. Litters were culled to 10 animals one day after birth and weaned at postnatal day (PN) 21 at which time they were fed the same diet as their corresponding mother||The length-density of the doublecortin-positive apical dendrites in the outer portion of the dentate gyrus molecular layer has been found significantly decreased up to 36% in chronically exposed rats||Verina et al., 2007|
|Lead||Wistar rats||Pregnant females received 0.1% lead acetate (PbAc) and led to blood levels of Pb2+ (10 ± 1.28 µg/dL) in pups||in utero and per os||Offspring (males and females) stayed with their mothers and were fed by them. During the feeding of pups, mothers from the experimental group were still receiving PbAc in drinking water ad libitum. Pups were weaned at postnatal day 21 (PND 21) and received only distilled water ad libitum until PND 28.||Decrease of BDNF concentration (pg/mg protein) that is 39% in forebrain cortex and 29% in hippocampus||Baranowska-Bosiacka et al., 2013|
|Lead||Primary hippocampal cultures were prepared from brains of SD rats at postnatal day 0 (P0)||0.1 µM and 1 µM||Exposure from DIV7 to DIV12||The dendritic spine density was significantly decreased about 25.84% and 42.70%, compared to the control group||Hu et al., 2014|
|Lead||Primary hippocampal cultures obtained from E18 Sprague-Dawley rat pups||1µM||Exposure from DIV7 to DIV12||Pb2+ exposure during synaptogenesis reduces cellular levels of proBDNF protein by 40% and reduces the amount of BDNF found in the neuron culture medium determined by ELISA by almost 30%||Neal et al., 2010|
|Lead||Primary hippocampal cultures obtained from E18 Sprague-Dawley rat pups||1 and 2µM||Exposure from DIV7 to DIV12||Quantitative real-time PCR of BDNF exon I, II, IV, and IX showed a significant effect of Pb2+ exposure on exons IV and IX transcripts with no effects on exons I and II (2 fold reduction compared to controls. Found significant reductions in dendritic proBDNF levels that were apparent throughout the length of the dendrites. Western blots confirmed that whole-cell proBDNF protein levels were significantly decreased after exposure to 1 and 2µM Pb2+ by 20 and 25%, respectively. In addition, extracellular levels of BDNF measured by ELISA were also significantly reduced by Pb2+ after exposure to 1 and 2µM Pb2+ by 40 and 60%, respectively.||Stansfield et al., 2012|
|Lead||Neural stem cells (NSCs) originating from E15 rat cortex (CX), striatum (ST) or ventral mesencephalon (VM).||0.1–10 µM||Neuro-spheres generated from NSCs originating in different brain regions were primed with lead acetate for 3 days and then dissociated into single cells and plated on poly-d-ornithine pre-coated chamber slides. Cells were allowed to grow in differentiation medium for 7 days with or without addition of lead acetate.||Lead exposure (0.1–10 µM) had no significant effect on MAP2 levels in CX-derived NSCs. Lead exposure decreased MAP-2-positive cells of ST and VM-derived NSCs at concentrations of 0.1–10 µM. VM-derived NSCs had the greatest sensitivity to the inhibitory effects of lead exposure causing 25% decrease in MAP-2-positive cells at 0.1 µM and almost 50% at 10 µM.||Huang and Schneider, 2004|
|Lead||D3 mouse ES (ES-D3) cells and 3T3 mouse embryonic fibroblast cells||0.3 to 30 µg/mL||Lead (II) acetate was applied to ES cells during neuronal differentiation||The number of MAP-2-positive cells decreased when more than 0.3 µg/mL of lead (II) acetate was applied and no MAP-2-positive cells were found when more than 30 µg/mL of lead (II) acetate was applied. Flow cytometry analysis of MAP-2-positive cells and real-time PCR analysis of MAP2 mRNA were performed to confirm the ID50 of neuronal differentiation in the presence of 0.3 to 30 µg/mL of lead (II) acetate. The ID50 value of lead (II) acetate as determined by flow cytometry was 12.75 . The ID50 of lead (II) acetate as determined by real-time PCR analysis was 5.09 µg/mL||Beak et al., 2011|
Uncertainties and Inconsistencies
Various molecular mechanisms have been identified as regulators of dendritic arborisation patterns and dendtitic spine formation (Jan and Jan, 2010). More specific, transcription factors, growth factors, receptor-ligand interactions, various signalling pathways, local translational machinery, cytoskeletal elements, Golgi outposts and endosomes have been identified as contributors to the organization of dendrites of individual neurons and the contribution of these dendrites in the neuronal circuitry (Jan and Jan, 2010). This study suggests that more parameters rather than only BDNF may be involved in dendritic arbor and spine formation during development.
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
In organotypic slice cultures derived from the ferret visual cortex application of exogenous BDNF increased the length and complexity especially of Layer IV pyramidal neurons (McAllister et al., 1995) that was also activity-dependent (McAllister et al., 1996). Several studies conducted in rodents further support that the in vitro treatment of hippocampal cultures with exogenous BDNF increases dendritic growth in developing neurons (reviewed in Zagrebelsky and Korte, 2014).
Alexis M, Stranahan AM. (2011) Physiological variability in brain-derived neurotrophic factor expression predicts dendritic spine density in the mouse dentate gyrus. Neurosci Lett. 495: 60-62.
Alfano DP, Petit TL. (1982) Neonatal lead exposure alters the dendritic development of hippocampal dentate granule cells. Exp Neurol. 75: 275-288.
An JJ, Gharami K, Liao GY, Woo NH, Lau AG, Vanevski F, Torre ER, Jones KR, Feng Y, Lu B, Xu B. (2008) Distinct role of long 3' UTR BDNF mRNA in spine morphology and synaptic plasticity in hippocampal neurons. Cell 134: 175-187.
Baek DH, Park SH, Park JH, Choi Y, Park KD, Kang JW, Choi KS, Kim HS. (2011) Embryotoxicity of lead (II) acetate and aroclor 1254 using a new end point of the embryonic stem cell test. Int J Toxicol. 30: 498-509.
Baranowska-Bosiacka I, Strużyńska L, Gutowska I, Machalińska A, Kolasa A, Kłos P, Czapski GA, Kurzawski M, Prokopowicz A, Marchlewicz M, Safranow K, Machaliński B, Wiszniewska B, Chlubek D. (2013) Perinatal exposure to lead induces morphological, ultrastructural and molecular alterations in the hippocampus. Toxicology 303: 187-200.
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.
Harvey CD, Yasuda R, Zhong H, Svoboda K. (2008) The spread of Ras activity triggered by activation of a single dendritic spine. Science. 321: 136-140.
Hiester BG, Galati DF, Salinas PC, Jones KR. (2013) Neurotrophin and Wnt signaling cooperatively regulate dendritic spine formation. Mol Cell Neurosci. 56: 115-127.
Hu F, Xu L, Liu Z-H, Ge M-M, Ruan D-Y, et al. (2014) Developmental Lead Exposure Alters Synaptogenesis through Inhibiting Canonical Wnt Pathway In Vivo and In Vitro. PLoS ONE 9(7): e101894.
Huang F, Schneider JS. (2004) Effects of lead exposure on proliferation and differentiation of neural stem cells derived from different regions of embryonic rat brain. Neurotoxicology 25: 1001–1012.
Jan YN, Jan LY (2010). Branching out: mechanisms of dendritic arborization. Nat Rev Neurosci. 11: 316-328.
Kang H, Schuman EM. (1996) A requirement for local protein synthesis in neurotrophin-induced hippocampal synaptic plasticity. Science 273: 1402-1406.
Kwon M, Fernández JR, Zegarek GF, Lo SB, Firestein BL. (2011) BDNF-promoted increases in proximal dendrites occur via CREB-dependent transcriptional regulation of cypin. J Neurosci. 31: 9735-9745.
McAllister AK, Lo DC, Katz LC. (1995) Neurotrophins regulate dendritic growth in developing visual cortex. Neuron 15: 791-803.
McAllister AK, Katz LC, Lo DC. (1996) Neurotrophin regulation of cortical dendritic growth requires activity. Neuron 17: 1057-1064.
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.
Park H, Poo MM. (2013) Neurotrophin regulation of neural circuit development and function. Nat Rev Neurosci 14: 7-23.
Sala C, Piech V, Wilson NR, Passafaro M, Liu G, Sheng M. (2001) Regulation of dendritic spine morphology and synaptic function by Shank and Homer. Neuron 31: 115-130.
Schratt GM, Nigh EA, Chen WG, Hu L, Greenberg ME. (2004) BDNF regulates the translation of a select group of mRNAs by a mammalian target of rapamycin-phosphatidylinositol 3-kinase-dependent pathway during neuronal development. J Neurosci. 24: 7366-7377.
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.
Tanaka JI, Horiike Y, Matsuzaki M, Miyazaki T, Ellis-Davies GCR, Kasai H. (2008) Protein synthesis and neurotrophin-dependent structural plasticity of single dendritic spines Science 319: 1683-1687.
Tyler WJ, Pozzo-Miller L. (2003) Miniature synaptic transmission and BDNF modulate dendritic spine growth and form in rat CA1 neurones. J Physiol 553: 497-509.
Verina T, Rohde CA, Guilarte TR. (2007). Environmental lead exposure during early life alters granule cell neurogenesis and morphology in the hippocampus of young adult rats. Neuroscience 145: 1037-1047.
Waterhouse EG, Xu B. (2009) New insights into the role of brain-derived neurotrophic factor in synaptic plasticity. Mol Cell Neurosci. 42: 81-89.
Yin Y, Edelman GM, Vanderklish PW. (2002) The brain-derived neurotrophic factor enhances synthesis of Arc in synaptoneurosomes. Proc Natl Acad Sci USA. 99: 2368-2373.
Zagrebelsky M, Korte M. (2014) Form follows function: BDNF and its involvement in sculpting the function and structure of synapses. Neuropharmacology. 76 PtC: 628-638.